Indazole derivatives

ABSTRACT

The present invention provides a compound represented by Formula (I):  
                 
 
[wherein R 1  represents CONR 1a R 1b  (wherein R 1a  and R 1b  may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted ararkyl or a substituted or unsubstituted heterocyclic group, or R 1a  and R 1b  are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group) or the like, 
     R 2  represents a hydrogen atom, CONR 2a R 2b  (wherein R 2a  and R 2b  may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted ararkyl or a substituted or unsubstituted heterocyclic group, or R 2a  and R 2b  are combined together with the adjacent nitrogen atom thereto to form a substituted or unsubstituted heterocyclic group), NR 2c R 2d  (wherein R 2c  and R 2d  may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted aroyl, substituted or unsubstituted heteroaroyl, substituted or unsubstituted ararkyl, substituted or unsubstituted lower alkylsulfonyl or substituted or unsubstituted lower arylsulfonyl) or the like].

TECHNICAL FIELD

The present invention relates to indazole derivatives orpharmaceutically acceptable salts thereof which have antitumoractivities or the like.

BACKGROUND ART

As indazole derivatives, various compounds have been known [JapanesePublished Unexamined Patent Application (Kokai) No. 32059/1990; WO01/53268; WO 02/10137; and Khimiya Geterotsiklicheskikh Soedinenii, vol.7, pages 957-959 (1978)].

In Japanese published Unexamined Patent Application (Kokai) No.32059/1990, compounds represented by Formula (II)

{wherein R^(3A) represents a hydrogen atom, nitro, NR^(3A1)R^(3A2)[wherein R^(3A1) and R^(3A2) may be the same or different and eachrepresents a hydrogen atom, substituted or unsubstituted lower alkyl(the carbon number in the lower alkyl is 1 to 6), lower alkanoyl (thecarbon number in the lower alkanoyl is 1 to 6) or the like] or the like,R^(4A) represents a hydrogen atom or the like, Ar represents pyridyl,substituted or unsubstituted 2-oxochromenyl [the 2-oxochromenyl isbonded to ethenyl (—CH═CH—) on its benzene ring, and the substituent(s)on the 2-oxochromenyl is lower alkyl having 1 to 6 carbon atom(s) orlower alkoxy having 1 to 6 carbon atom(s)], or substituted orunsubstituted phenyl [substituents Q^(5A1), Q^(5A2) and Q^(5A3) in thesubstituted phenyl may be the same or different and each represents ahydrogen atom, halogen, nitro, nitroso, hydroxy, carboxy, lower alkylhaving 1 to 6 carbon atom(s), lower alkoxy having 1 to 6 carbon atom(s),lower alkoxycarbonyl having 1 to 6 carbon atom(s), NR^(5A1)R^(5A2)(wherein R^(5A1) and R^(5A2) have the same meanings as R^(3A1) andR^(3A2) defined above, respectively), or O(CH₂)_(nd)NR^(5A3)R^(5A4)(wherein nd represents an integer of 1 to 6 and R^(5A3) and R^(5A4) havethe same meanings as R^(3A1) and R^(3A2) defined above, respectively),or any two from the groups Q^(5A1) to Q^(5A3) are combined together toform —O(CR^(5A5)R^(5A6))O— (wherein two terminal oxygen atoms are bondedto the phenyl at adjacent carbon atoms on the phenyl and R^(5A5) andR^(5A6) may be the same or different and each represents a hydrogen atomor lower alkyl having 1 to 6 carbon atom(s), or R^(5A5) and R^(5A6) arecombined together to form alkylene having 4 or 5 carbon atoms), providedthat the Q^(5A1), Q^(5A2) and Q^(5A3) which are the substituents in thesubstituted phenyl are not simultaneously hydrogen atoms]) aredisclosed.

In WO 01/53268, compounds having suppressive activity on celldifferentiation represented by Formula (III)

[wherein R^(5B) represents CH═CH—R^(5B1) (wherein R^(5B1) representssubstituted or unsubstituted alkyl, substituted or unsubstituted aryl, asubstituted or unsubstituted heterocyclic group or the like) and R^(3B)represents alkyl, aryl, CH═CH—R^(5B2) (wherein R^(5B2) representssubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl or the like)] are disclosed.

In WO 02/10137, compounds having inhibitory activity against c-junN-terminal Kinase (JNK) represented by Formula (IV)

[wherein R^(5C) represents CH═CH—R^(5C1) (wherein R^(5C1) representssubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl or the like) and R^(3C) represents halogen, hydroxy, amino orthe like] are disclosed.

In Khimiya Geterotsiklicheskikh Soedinenii, vol. 7, pages 957-959(1978), compounds represented by Formula (V)

(wherein R^(1D) represents methoxy or nitro) are disclosed.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide indazole derivatives orpharmaceutically acceptable salts thereof which are useful as anantitumor agent or the like.

The present invention relates to following (1) to (24).

(1) An indazole derivative represented by Formula (I)

[wherein R¹ represents CONR^(1a)R^(1b) (wherein R^(1a) and R^(1b) may bethe same or different and each represents a hydrogen atom, substitutedor unsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted aralkyl, or a substituted or unsubstitutedheterocyclic group, or R^(1a) and R^(1b) are combined together with theadjacent nitrogen atom thereto to form a substituted or unsubstitutedheterocyclic group) or NR^(1c)R^(1d) (wherein R^(1c) representssubstituted or unsubstituted lower alkylsulfonyl or substituted orunsubstituted arylsulfonyl and R^(1d) represents a hydrogen atom orsubstituted or unsubstituted lower alkyl) and

-   R² represents a hydrogen atom, halogen, cyano, nitro, hydroxy,    carboxy, lower alkoxycarbonyl, substituted or unsubstituted lower    alkyl, substituted or unsubstituted lower alkoxy, substituted or    unsubstituted lower alkanoyl, CONR^(2a)R^(2b) (wherein R^(2a) and    R^(2b) may be the same or different and each represents a hydrogen    atom, substituted or unsubstituted lower alkyl, substituted or    unsubstituted aryl, substituted or unsubstituted aralkyl or a    substituted or unsubstituted heterocyclic group, or R^(2a) and    R^(2b) are combined together with the adjacent nitrogen atom thereto    to form a substituted or unsubstituted heterocyclic group) or    NR^(2c)R^(2d) (wherein R^(2c) and R^(2d) may be the same or    different and each represents a hydrogen atom, substituted or    unsubstituted lower alkyl, substituted or unsubstituted lower    alkanoyl, substituted or unsubstituted aroyl, substituted or    unsubstituted heteroaroyl, substituted or unsubstituted aralkyl,    substituted or unsubstituted lower alkylsulfonyl or substituted or    unsubstituted arylsulfonyl)], or a pharmaceutically acceptable salt    thereof.

(2) The indazole derivative or the pharmaceutically acceptable saltthereof according to (1), wherein R¹ is CONR^(1a)R^(1b) (wherein R^(1a)and R^(1b) have the same meanings as defined above, respectively) and R²is a hydrogen atom or substituted or unsubstituted lower alkoxy.

(3) The indazole derivative or the pharmaceutically acceptable saltthereof according to (1), wherein R¹ is NR^(1c)R^(1d) (wherein R^(1c)and R^(1d) have the same meanings as defined above, respectively) and R²is substituted or unsubstituted lower alkoxy.

(4) The indazole derivative or the pharmaceutically acceptable saltthereof according to (1), wherein R¹ is CONR^(1a)R^(1b) (wherein R^(1a)and R^(1b) have the same meanings as defined above, respectively) and R²is halogen or substituted or unsubstituted lower alkyl.

(5) The indazole derivative or the pharmaceutically acceptable saltthereof according to (1), wherein R¹ is NR^(1c)R^(1d) (wherein R^(1c)and R^(1d) have the same meanings as defined above, respectively) and R²is a hydrogen atom.

(6) A pharmaceutical composition which comprises, as an activeingredient, the indazole derivative or the pharmaceutically acceptablesalt thereof according to any of (1) to (5).

(7) An antitumor agent which comprises, as an active ingredient, theindazole derivative or the pharmaceutically acceptable salt thereofaccording to any of (1) to (5).

(8) A therapeutic agent for hematopoietic tumor which comprises, as anactive ingredient, the indazole derivative or the pharmaceuticallyacceptable salt thereof according to any of (1) to (5).

(9) A therapeutic agent for leukemia which comprises, as an activeingredient, the indazole derivative or the pharmaceutically acceptablesalt thereof according to any of (1) to (5).

(10) A therapeutic agent for myeloma or lymphoma which comprises, as anactive ingredient, the indazole derivative or the pharmaceuticallyacceptable salt thereof according to any of (1) to (5).

(11) A therapeutic agent for solid carcinoma which comprises, as anactive ingredient, the indazole derivative or the pharmaceuticallyacceptable salt thereof according to any of (1) to (5).

(12) A therapeutic agent for cancer derived from mammary cancer, uterinebody cancer, uterine cervix cancer, prostatic cancer, bladder cancer,renal cancer, gastric cancer, esophageal cancer, hepatic cancer, biliarytract cancer, colon cancer, rectal cancer, pancreatic cancer, lungcancer, oral cavity and pharynx cancer, osteosarcoma, melanoma or brainneoplasm, which comprises, as an active ingredient, the indazolederivative or the pharmaceutically acceptable salt thereof according toany of (1) to (5).

(13) Use of the indazole derivative or the pharmaceutically acceptablesalt thereof according to any of (1) to (5) for the manufacture of anantitumor agent.

(14) Use of the indazole derivative or the pharmaceutically acceptablesalt thereof according to any of (1) to (5) for the manufacture of atherapeutic agent for hematopoietic tumor.

(15) Use of the indazole derivative or the pharmaceutically acceptablesalt thereof according to any of (1) to (5) for the manufacture of atherapeutic agent for leukemia.

(16) Use of the indazole derivative or the pharmaceutically acceptablesalt thereof according to any of (1) to (5) for the manufacture of atherapeutic agent for myeloma or lymphoma.

(17) Use of the indazole derivative or the pharmaceutically acceptablesalt thereof according to any of (1) to (5) for the manufacture of atherapeutic agent for solid carcinoma.

(18) Use of the indazole derivative or the pharmaceutically acceptablesalt thereof according to any of (1) to (5) for the manufacture of atherapeutic agent for cancer derived from mammary cancer, uterine bodycancer, uterine cervix cancer, prostatic cancer, bladder cancer, renalcancer, gastric cancer, esophageal cancer, hepatic cancer, biliary tractcancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer,oral cavity and pharynx cancer, osteosarcoma, melanoma or brainneoplasm.

(19) A method for treating tumor, comprising a step of administering aneffective amount of the indazole derivative or the pharmaceuticallyacceptable salt thereof according to any of (1) to (5).

(20) A method for treating hematopoietic tumor, comprising a step ofadministering an effective amount of the indazole derivative or thepharmaceutically acceptable salt thereof according to any of (1) to (5).

(21) A method for treating leukaemia, comprising a step of administeringan effective amount of the indazole derivative or the pharmaceuticallyacceptable salt thereof according to any of (1) to (5).

(22) A method for treating myeloma or lymphoma, comprising a step ofadministering an effective amount of the indazole derivative or thepharmaceutically acceptable salt thereof according to any of (1) to (5).

(23) A method for treating solid carcinoma, comprising a step ofadministering an effective amount of the indazole derivative or thepharmaceutically acceptable salt thereof according to any of (1) to (5).

(24) A method for treating cancer derived from mammary cancer, uterinebody cancer, uterine cervix cancer, prostatic cancer, bladder cancer,renal cancer, gastric cancer, esophageal cancer, hepatic cancer, biliarytract cancer, colon cancer, rectal cancer, pancreatic cancer, lungcancer, oral cavity and pharynx cancer, osteosarcoma, melanoma or brainneoplasm, comprising a step of administering an effective amount of theindazole derivative or the pharmaceutically acceptable salt thereofaccording to any of (1) to (5).

The compounds represented by General Formula (I) are hereinafterreferred to as Compound (I). The same is true for compounds representedby other formula number.

In the definitions for each groups in Formula (I):

-   -   (i) The halogen includes fluorine, chlorine, bromine, and iodine        atoms.    -   (ii) Examples of the lower alkyl and the lower alkyl moieties of        the lower alkoxy, the lower alkoxycarbonyl and the lower        alkylsulfonyl include, for example, linear, branched or cyclic        alkyl or alkyl comprising these alkyls in combination, having 1        to 10 carbon atom(s). More specific examples thereof are as        follows.        -   (ii-a) Examples of the linear or branched lower alkyl            include, for example, methyl, ethyl, n-propyl, isopropyl,            n-butyl, isobutyl, se c-butyl, tert-butyl, n-pentyl,            neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl;        -   (ii-b) examples of the cyclic lower alkyl include, for            example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,            cycloheptyl, cyclooctyl, cyclodecyl, noradamantyl,            adamantyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,            bicyclo[3.3.0]octyl and bicyclo[3.3.1]nonyl; and        -   (ii-c) examples of the lower alkyl comprising linear or            branched alkyl and cyclic alkyl include, for example,            cyclopropylmethyl, cyclopentylmethyl and cyclooctylethyl.    -   (iii) The alkylene moiety of the aralkyl has the same meaning as        the group formed by removing one hydrogen atom from the linear        or branched lower alkyl (ii-a) in the definition of the lower        alkyl defined above.    -   (iv) Examples of the aryl and the aryl moieties of the aroyl,        the arylsulfonyl and the aralkyl include, for example,        monocyclic aryls or fused aryl in which two or more rings are        fused, and more specific examples include aryl having 6 to 14        carbon atoms as ring-constituting members, such as phenyl,        naphthyl, indenyl or anthranyl.    -   (v) Examples of the lower alkanoyl include, for example, linear,        branched, or cyclic lower alkanyol, or lower alkanoyl comprising        these lower alkanoyls in combination, having 1 to 8 carbon        atom(s), such as formyl, acetyl, propionyl, butyryl, isobutyryl,        valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl,        cyclopropylcarbonyl, cyclobutylcarbonyl,        cyclopropylmethylcarbonyl, cyclopentylcarbonyl,        cyclohexylcarbonyl, 1-methylcyclopropylcarbonyl or        cycloheptylcarbonyl.    -   (vi) Examples of the heterocyclic group include, for example,        heteroaromatic group and heteroalicyclic group. Examples of the        heteroaromatic group include, for example, monocyclic aromatic        heterocyclic group or fused heteroaromatic group in which two or        more rings are fused. The type and number of the heteroatom        contained in heteroaromatic group are not specifically limited        and the heteroaromatic group may contain, for example, one or        more heteroatoms selected from the group consisting of nitrogen        atom, sulfur atom and oxygen atom. More specific examples        include heteroaromatic group having 5 to 14 carbon atoms as        ring-constituting members, such as furyl, thienyl, pyrrolyl,        imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,        oxadiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl,        pyridazinyl, triazinyl, indolyl, indazolyl, benzimidazolyl,        benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl,        phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,        cinnolinyl, purinyl or coumarinyl. Examples of the        heteroalicyclic group include, for example, monocyclic        heteroalicyclic group or fused heteroalicyclic group in which        two or more rings are fused. The type and number of the        heteroatom contained in heteroalicyclic groups are not        specifically limited and the heteroalicyclic group may contain,        for example, one or more heteroatoms selected from the group        consisting of nitrogen atom, sulfur atom and oxygen atom. More        specific examples include, for example, pyrrolidinyl,        thiazolidinyl, oxazolidinyl, piperidyl, 1,2-dihydropyridyl,        piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl,        pyrazolinyl, oxazolinyl, dioxolanyl, tetrahydropyranyl,        tetrahydrothiopyranyl, tetrahydrofuryl, tetrahydroquinolyl,        tetrahydroisoquinolyl, tetrahydroquinoxalinyll        octahydroquinolyl, indolinyl and isoindolinyl.    -   (vii) Examples of the heterocyclic group formed together with        the adjacent nitrogen atom include 5- or 6-membered monocyclic        heteroalicyclic group containing at least one nitrogen atom (the        monocyclic heteroalicyclic group may further contain any other        of a nitrogen atom, an oxygen atom and a sulfur atom) and        bicyclic or tricyclic fused heterocyclic group containing at        least one nitrogen atom in which 3- to 8-membered rings are        fused (the fused heterocyclic group may further contain any        other of a nitrogen atom, an oxygen atom and a sulfur atom).        More specific examples include, for example, pyrrolidinyl,        pyrrolidonyl, piperidino, piperazinyl, morpholino,        thiomorpholino, homopiperidino, homopiperazinyl,        tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolyl,        indolyl and isoindolyl.    -   (viii) The heteroaryl moiety in the heteroaroyl has the same        meaning as the heteroaromatic group in the heterocyclic        group (vi) defined above.    -   (ix) Examples of the substituents in the substituted lower        alkyl, the substituted lower alkoxy, the substituted lower        alkylsulfonyl and the substituted lower alkanoyl, which may be        the same or different and in number of 1 to 3, include    -   (ix-a) hydroxy,    -   (ix-b) oxo,    -   (ix-c) carboxy,    -   (ix-d) lower alkoxy,    -   (ix-e) lower alkoxycarbonyl,    -   (ix-f) arylsulfonyl,    -   (ix-g) heteroaroyl,    -   (ix-h) substituted or unsubstituted aryl (the substituent(s) in        the substituted aryl, which is 1 to 3 in number, is for example,        carboxy, lower alkoxycarbonyl, methylenedioxy and        ethylenedioxy),    -   (ix-i) a substituted or unsubstituted heterocyclic group [the        substituent(s) (ix-ia) in the substituted heterocyclic group,        which is 1 to 3 in number, is for example, lower alkyl, lower        alkoxy and lower alkanoyl, and when the substituted heterocyclic        group is a substituted heteroalicyclic group, the substituent        may be oxo],    -   (ix-j) NR^(6a)R^(6b) [wherein R^(6a) and R^(6b) may be the same        or different and each represents a hydrogen atom, substituted or        unsubstituted lower alkyl (the substituent(s) in the substituted        lower alkyl, which is 1 to 3 in number, is for example, halogen,        hydroxy or lower alkoxy) or substituted or unsubstituted lower        alkanoyl (the substituent(s) in the substituted lower alkanoyl,        which is 1 to 3 in number, is for example, halogen, hydroxy,        lower alkoxy or aryl) or R^(6a) and R^(6b) are combined together        with the adjacent nitrogen atom thereto to form a heterocyclic        group],    -   (ix-k) CONR^(7a)R^(7b) (wherein R^(7a) and R^(7b) have the same        meanings as R^(6a) and R^(6b) defined above, respectively) and    -   (ix-l) lower alkoxy-lower alkoxy.

In the definition of the substituents (ix) in the substituted loweralkyl, the substituted lower alkoxy, the substituted lower alkylsulfonyland the substituted lower alkanoyl, the halogen has the same meaning as(i) defined above; the lower alkyl and the lower alkyl moiety of thelower alkoxy, the lower alkoxycarbonyl and the lower alkoxy-lower alkoxyhave the same meanings as (ii) defined above, respectively; the alkylenemoiety of the lower alkoxy-lower alkoxy has the same meaning as thegroup formed by removing one hydrogen atom from the linear or branchedlower alkyl (ii-a) in the definition of the lower alkyl defined above;the aryl and the aryl moiety of the arylsulfonyl have the same meaningsas (iv) defined above, respectively; the lower alkanoyl has the samemeaning as (v) defined above; the heterocyclic group has the samemeaning as (vi) defined above; the heterocyclic group formed togetherwith the adjacent nitrogen atom has the same meaning as (vii) definedabove; and the heteroaroyl has the same meaning (viii) defined above.

-   -   (x) Examples of the substituents in the substituted aryl, the        substituted ardyl, the substituted aralkyl, the substituted        arylsulfonyl, the substituted heteroaroyl, the substituted        heterocyclic group and the substituted heterocyclic group formed        together with the adjacent nitrogen atom, which may be the same        or different and is 1 to 3 in number, include    -   (x-a) halogen,    -   (x-b) hydroxy,    -   (x-c) nitro,    -   (x-d) cyano,    -   (x-e) formyl,    -   (x-f) carboxy,    -   (x-g) lower alkoxycarbonyl,    -   (x-h) substituted or unsubstituted lower alkyl [the        substituent(s) in the substituted lower alkyl has the same        meaning as (ix) defined above],    -   (x-i) substituted or unsubstituted lower alkoxy [the        substituent(s) in the substituted lower alkoxy has the same        meaning as (ix) defined above],    -   (x-j) substituted or unsubstituted lower alkanoyl [the        substituent(s) in the substituted lower alkanoyl has the same        meaning as (ix) defined above],    -   (x-k) substituted or unsubstituted lower alkylsulfonyl [the        substituent(s) in the substituted lower alkylsulfonyl has the        same meaning as (ix) defined above],    -   (x-l) substituted or unsubstituted aroyl [the substituent(s)        (x-la) in the substituted aroyl, which is 1 to 3 in number, is        for example, halogen, hydroxy, nitro, cyano, carboxy, lower        alkanoyl, lower alkoxycarbonyl, aralkyl, aroyl, substituted or        unsubstituted lower alkyl (the substituent(s) in the substituted        lower alkyl, which is 1 to 3 in number, is for example hydroxy)        and substituted or unsubstituted lower alkoxy (the        substituent(s) in the substituted lower alkoxy, which is 1 to 3        in number, is for example hydroxy),    -   (x-m) substituted or unsubstituted heteroaroyl [the        substituent(s) in the substituted heteroaroyl has the same        meaning as (x-la) defined above],    -   (x-n) substituted or unsubstituted aryl [the substituent(s) in        the substituted aryl has the same meaning as (x-la) defined        above],    -   (x-o) a substituted or unsubstituted heterocyclic group [the        substituent(s) in the substituted heterocyclic group has the        same meaning as (ix-ia) defined above],    -   (x-p) NR^(8a)R^(8b) (wherein R^(8a) and R^(8b) may be the same        or different and each represents a hydrogen atom, mono- or        di-(lower alkyl)aminocarbonyl, substituted or unsubstituted        lower alkyl [the substituent(s) in the substituted lower alkyl        has the same meaning as (ix) defined above], substituted or        unsubstituted lower alkanoyl [the substituent(s) in the        substituted lower alkanoyl has the same meaning as (ix) defined        above], substituted or unsubstituted lower alkoxycarbonyl [the        substituent(s) in the substituted lower alkoxycarbonyl has the        same meaning as (ix) defined above], substituted or        unsubstituted aryl [the substituent(s) in the substituted aryl        has the same meaning as (x-la) defined above], substituted or        unsubstituted aroyl [the substituent(s) in the substituted aroyl        has the same meaning as (x-la) defined above] or substituted or        unsubstituted heteroalicyclic carbonyl [the substituent(s) in        the substituted heteroalicyclic carbonyl, which is 1 to 3 in        number, is for example, halogen, hydroxy, oxo, amino, nitro,        cyano, carboxy, lower alkanoyl, lower alkoxycarbonyl, aralkyl,        aroyl, substituted or unsubstituted lower alkyl (wherein the        substituent(s) in the substituted lower alkyl, which is 1 to 3        in number, is for example hydroxy), substituted or unsubstituted        lower alkoxy (the substituent(s) in the substituted lower        alkoxy, which is 1 to 3 in number, is for example hydroxy)] or        R^(8a) and R^(8b) are combined together with the adjacent        nitrogen atom thereto to form a substituted or unsubstituted        heterocyclic group [the substituent(s) in the substituted        heterocyclic group formed with the adjacent nitrogen atom, which        is 1 to 3 in number, is for example, halogen, hydroxy, oxo,        amino, nitro, cyano, carboxy, lower alkanoyl, lower        alkoxycarbonyl, aralkyl, aroyl, substituted or unsubstituted        lower alkyl (the substituent(s) in the substituted lower alkyl,        which is 1 to 3 in number, is for example hydroxy) or        substituted or unsubstituted lower alkoxy (the substituent(s) in        the substituted lower alkoxy, which is 1 to 3 in number, is for        example hydroxy)]},    -   (x-q) CONR^(9a)R^(9b) (wherein R^(9a) and R^(9b) have the same        meanings as R^(8a) and R^(8b) defined above, respectively),    -   (x-r) substituted or unsubstituted arylsulfonyl [the        substituent(s) in the substituted arylsulfonyl has the same        meaning as (x-la) defined above],    -   (x-s) substituted or unsubstituted lower cycloalkenyl {the        substituent(s) in the substituted lower cycloalkenyl, which is 1        to 3 in number, is for example, amino, oxo, mono- or di-(lower        alkyl)amino, or a substituted or unsubstituted heterocyclic        group [the substituent(s) in the substituted heterocyclic group        has the same meaning as (x-la) defined above])} and    -   (x-t) substituted or unsubstituted heteroalicyclic carbonyl [the        substituent(s) in the substituted heteroalicyclic carbonyl,        which is 1 to 3 in number, is for example, halogen, hydroxy,        oxo, amino, nitro, cyano, carboxy, lower alkanoyl, lower        alkoxycarbonyl, aralkyl, aroyl, substituted or unsubstituted        lower alkyl (the substituent(s) in the substituted lower alkyl,        which is 1 to 3 in number, is for example hydroxy) or a        substituted or unsubstituted lower alkoxy (the substituent(s) in        the substituted lower alkoxy, which is 1 to 3 in number, is for        example hydroxy)].

The substituent(s) in the substituted heteroalicyclic group, and thesubstituent(s) in the substituted heterocyclic group formed with theadjacent nitrogen atom may be, in addition to (x-a) to (x-t), thefollowing (x-u) or (x-v):

-   -   (x-u) oxo    -   (x-v) —O(CR^(10a)R^(10b))_(n)O— (wherein R^(10a) and R^(10b) may        be the same or different and each represents a hydrogen atom,        lower alkyl or the like, n represents 2 or 3, and the two        terminal oxygen atoms are combined on the same carbon atom in        the substituted heterocyclic group formed with the adjacent        nitrogen atom)

In the definition of the substituents (x) in the substituted aryl, thesubstituted aroyl, the substituted aralkyl, the substitutedarylsulfonyl, the substituted heteroaroyl, the substituted heterocyclicgroup and the substituted heterocyclic group formed with the adjacentnitrogen atom, the halogen has the same meaning as (i) defined above;the lower alkyl and the lower alkyl moiety in the lower alkoxy, thelower alkoxycarbonyl, the lower alkylsulfonyl, the mono- or di-(loweralkyl)amino and the mono- or di-(lower alkyl)aminocarbonyl have the samemeanings as (ii) defined above, respectively, and the two lower alkylmoieties in the di-(lower alkyl)amino and the di-(loweralkyl)aminocarbonyl may be the same or different; the alkylene moiety inthe aralkyl has the same meaning as (iii) defined above; the aryl andthe aryl moiety in the aralkyl, the aroyl and the arylsulfonyl have thesame meanings as (iv) defined above, respectively; the lower alkanoylhas the same meaning as (v) defined above; the heterocyclic group hasthe same meaning as (vi) defined above; the heterocyclic group formedwith the adjacent nitrogen atom has the same meaning as (vii) definedabove; the heteroaryl moiety in the heteroaroyl has the same meaning as(viii) defined above; and the heteroalicyclic moiety in theheteroalicyclic carbonyl has the same meaning as the heteroalicyclicgroup in the heterocyclic group (vi) defined above. Examples of thelower cycloalkenyl include, for example, cycloalkenyl having 4 to 8carbon atoms, such as cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl.

Examples of the pharmaceutically acceptable salts of Compound (I)include, for example, pharmaceutically acceptable acid addition salts,metal salts, ammonium salts, organic amine addition salts, and aminoacid addition salts. The acid addition salts include, for example,inorganic acid salts such as hydrochlorides, sulfates and phosphates;and organic acid salts such as acetate, maleate, fumarate, tartrates,citrates, lactates, aspartates, and glutamates. The metal salts include,for example, alkali metal salts such as sodium salts and potassiumsalts; alkaline earth metal salts such as magnesium salts and calciumsalts; as well as aluminum salts and zinc salts. The ammonium saltsinclude, for example, salts of ammonium and tetramethylammonium. Theorganic amine addition salts include, for example, morpholine salts andpiperidine salts. The amino acid addition salts include, for example,lysine salts, glycine salts and phenylalanine salts.

The hematopoietic tumor refers to tumors typically in hemocytes.Examples of pathosis based on the hematopoietic tumor are leukemia suchas chronic myeloid leukemia and acute myeloid leukemia; myeloma such asmultiple myeloma; and lymphoma.

Production methods of Compound (I) will be described below.

Me, Et, Pr, ^(i)Pr, ^(i)Bu, ^(t)Bu, and Ph in the following reactionprocesses, structural formulae and tables represent methyl, ethyl,propyl, isopropyl, isobutyl, tert-butyl, and phenyl, respectively. Thedefinitions of each groups in the following reaction processes have thesame meanings as each groups defined above, unless otherwise noted.

When a defined group changes under the reaction conditions or is notsuitable for carrying out the method in the following productionmethods, it is possible to obtain the targeted compound using a methodfor introduction and elimination of protective group commonly used insynthetic organic chemistry [for example, Protective Groups in OrganicSynthesis, third edition, T. W. Greene, John Wiley & Sons Inc. (1999)].If necessary, the order of reaction processes such as introduction ofsubstituents can be changed.

Compound (I) can be produced according to the following reactionprocesses.

Production Method 1

Compound (I) can be produced using Compound (A) obtained in a similarmanner to the known method [e.g., J. Org. Chem., vol. 52, page 19(1987); Can. J. Chem., vol. 51, page 792 (1973)] according to thefollowing process:

(wherein X represents each atoms of chlorine, bromine or iodine and R¹and R² have the same meanings as defined above, respectively)Step 1

Compound (I) can be obtained by reacting Compound (A) with Compound (B)in the presence of a base, in a solvent such as methanol, ethanol,tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and mixtures ofthese solvents.

Potassium carbonate, potassium tert-butoxide, and sodium hydride may beused as the base. To Compound (A), 1 to 10 equivalent(s) of Compound (B)and the base are used, respectively. The reaction is usually performedat temperatures between 0 and 100° C. for 1 to 72 hours.

Production Method 2

Among Compound (I), Compound (Ia) which have a specific functional groupin R¹ or R² may also be produced using Compound (C) which have otherfunctional group in R¹ or R² obtained according to Production Method 1or other known method (for example, Japanese Published Unexamined PatentApplication (kokai) No. 32059/1990) according to the following process.

Although all the compounds mentioned as Compound (Ia) and the like inthe following steps, are not always included in the scope of Compound(I), they are indicated as, for example, Compound (Ia) for the sake ofconvenience. Further, even among compounds called here Compound (C) inthe following Steps 2-1 to 2-5, there are compounds included in Compound(I).

(wherein R^(1e), R^(1f), R^(2e) and R^(2f) represent the groups definedin following Steps 2-1 to 2-5, respectively. R^(1e) and R^(1f) have thesame meanings as R¹ defined above, respectively and R^(2e) and R^(2f)have the same meaning as R² defined above, respectively, unlessotherwise defined in following Steps 2-1 to 2-5)Step 2-1(In Step 2-1, at least one of R^(1e) and R^(2e) is lower alkoxycarbonyland at least one of R^(1f) and R^(2f) is carboxy)

Compound (Ia) can be obtained by subjecting Compound (C) to hydrolysisin water or in a mixed solvent of water and another solvent such asmethanol, ethanol or THF, in the presence of a base such as sodiumhydroxide or an acid such as hydrochloric acid.

To Compound (C), 0.1 to 10 equivalent(s) of the acid or the base ispreferably used. The reaction is usually performed at temperaturesbetween 20 and 100° C. for 1 to 72 hour(s).

Step 2-2

(In Step 2-2, at least one of R^(1e) and R^(2e) is nitro and at leastone of R^(1f) and R^(2f) is amino)

Compound (Ia) can be obtained by treating Compound (C) with a reducingagent such as tin or iron in the presence of an acid such asconcentrated hydrochloric acid or acetic acid in a solvent such aswater, ethanol or a mixed solvent thereof, or in the absence of thesolvent, or by subjecting Compound (C) to reduction in the presence of acatalyst such as palladium/carbon, platinum dioxide or Raney nickel inan atmosphere of hydrogen gas or in the presence of a hydrogen donorsuch as hydrazine hydrate or ammonium formate in a solvent such aswater, methanol, ethanol, THF, DMF, or a mixed solvent thereof.

To Compound (C), 1 to 100 equivalent(s) of the acid such as concentratedhydrochloric acid or acetic acid and 1 to 20 equivalent(s) of thereducing agent such as tin or iron are preferably used. To Compound (C),0.5 to 100 weight % of the catalyst and 1 to 100 equivalent(s) of thehydrogen donor are preferably used. The reaction is usually performed attemperatures between 0 to 100° C. for 1 to 72 hours.

Step 2-3

[In the Step 2-3, at least one of R^(1e) and R^(2e) is carboxy and atleast one of R^(1f) and R^(2f) is CONR¹⁰OR¹¹ (wherein R¹⁰ and R¹¹ havethe same meanings as R^(1a) and R^(1b) defined above, respectively)]

Compound (Ia) can be obtained by reacting Compound (C) with Compound (V)represented by HNR¹⁰R¹¹ (wherein R¹⁰ and R¹¹ have the same meanings asdefined above, respectively) in the presence of a condensing agent andan activating agent, in a solvent such as dichloromethane, THF,1,4-dioxane, DMF or N-methylpiperidone or a mixed solvent thereof.Examples of the condensing agent include dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,polymer-bound 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, andtriphenylphosphine oxide.trifluoromethanesulfonic anhydride. Examples ofthe activating agent include 1-hydroxybenzotriazole andN-hydroxysuccinimide.

To Compound (C), 1 to 20 equivalent(s) of the reducing agent, theactivating agent and Compound (V) are preferably used, respectively. Thereaction is usually performed at temperatures between −20 and 80° C. for30 minutes to 72 hours. Some of Compound (V) can be subjected to thereaction in the form of a salt formed by mixing with an activatingagent.

Step 2-4

[In the Step 2-4, at least one of R^(1e) and R^(2e) is amino and atleast one of R^(1f) and R^(2f) is NHSO₂R¹² (wherein R¹² representssubstituted or unsubstituted lower alkyl or substituted or unsubstitutedaryl)]

In the definition of R¹², the lower alkyl and the aryl have the samemeanings as (ii) and (iv) defined above, respectively. The substituentsin the substituted lower alkyl and the substituted aryl have the samemeanings as (ix) and (x) defined above, respectively.

Compound (Ia) can be obtained by reacting Compound (C) with Compound(VI) represented by R¹²SO₂Cl (wherein R¹² has the same meaning asdefined above) or Compound (VII) represented by (R¹²SO₂)₂O (wherein R¹²has the same meaning as defined above) in the presence of a base such astriethylamine, pyridine, p-dimethylaminopyridine, polyvinylpyridine,4-morpholinomethylpolystyrene or 4-piperidinopolystyrene, in a solventsuch as dichloromethane, THF, 1,4-dioxane, DMF, or N-methylpiperidone ora mixed solvent thereof.

To Compound (C), 1 to 20 equivalent(s) of the base and the Compound (VI)or Compound (VII) are preferably used, respectively. The reaction isusually performed at temperatures between −20 and 80° C. for 30 minutesto 24 hours.

Step 2-5

[In the Step 2-5, at least one of R^(1e) and R^(2e) is substituentincluding halogen and at least one of R^(1f) and R^(2f) is substituentincluding carboxy. The halogen has the same meaning as (i) definedabove]

Compound (Ia) can be obtained by treating Compound (C) with a strongbase such as sodium hydride or n-butyllithium in a solvent such as THF,and reacting the obtained compound with gaseous or solid carbon dioxide.

To Compound (C), 1 to 10 equivalent(s) of the strong base and 1 to 200equivalent(s) of carbon dioxide are preferably used, respectively. Thereaction is usually performed at temperatures between −80 and 30° C. for1 to 24 hours.

Transformation of functional groups contained in R¹ or R² in Compound(I) and the starting material can also be carried out by other knownmethods [for example, Comprehensive Organic Transformations, R. C.Larock, (1989)] in addition to the above processes.

Compound (I) having a desired functional group at a desired position canbe obtained by carrying out the above processes in any suitablecombination thereof.

Isolation and purification of the Products in the above-mentionedproduction methods can be carried out by an appropriate combination ofusual methods used in organic syntheses, such as filtration, extraction,washing, drying, concentration, crystallization and variouschromatography. Intermediates can also be use in the subsequent reactionstep without further purification.

There can be isomers such as positional isomers, geometrical isomers oroptical isomers in Compound (I). All possible isomers including theseisomers, and mixtures of the isomers in any ratio can be used in thepresent invention or included in the present invention.

When it is desired to obtain a salt of Compound (I), in the case whereit is obtained in a form of a salt, this may be purified as it is, whereit is obtained in a free form, it is dissolved or suspended in anappropriate solvent followed by adding an acid or a base thereto to forma salt.

Compound (I) or pharmaceutically acceptable salt thereof may exist inthe form of adducts with water or solvents. These adducts are alsoincluded in the present invention.

Specific examples of Compound (I) are shown in Table 1 which by no meanslimit the scope of the present invention. TABLE 1

Compound Number R^(A) R^(B) salt 1 CONMe₂ H 2 CONHCH₂CH₂CHMe₂ H 3CONHCH₂Ph H 4 CONHCH₂CH₂OMe H 5 CONMeCH₂CH₂OMe H 6 CONHCH₂CH₂NMe₂ H 7

NHSO₂Me 8

CONH₂ 9

H 10

H 11 CONH(CH₂)₂NHCOMe H 12

CONHMe 13

H 14 CONHMe H 15 CONEt₂ H HCl 16

H HCl 17

H 18

H 19

H 20

H 21

H 22

H 23

H 24

H 25

H 26

H HCl 27 H NHSO₂Me 28 H NHSO₂Ph HCl 29

H 30

H 31

H 32

H 33

H HCl 34

H HCl 35

H HCl 36 H

HCl 37 H

HCl 38 H CONH(CH₂)₂NHCOMe HCl 39

H 40

H 41

H 42

H 43

H 44

H 45

H 46

H 47

H 48

H 49

H 50

H 51

H 52 CONHCH₂CO₂Me H 53 CONHCH₂CO₂H H 54

OMe 55

H 56

H 57

H 58

H 59

H 60

H 61

H 2HCl 62

H 63 CONH(CH₂)₂NEt₂ H 64

H 65

H 66

H 67

H 68

H 69

Cl 70 CONHCH₂CONHMe H 71

H 72

H 73

Me 74

H HCl 75

H HCl 76

H HCl 77

H 78

H 79 CONH(CH₂)₂CO₂Et H 80

H 81

H 82

H 83

Cl 84

Me 85

H 2HCl 86

H 87

H 88

H 89

H 90

H 91

H 92

H 93 CONH(CH₂)₂CONEt₂ H 94 CONHCH₂CONEt₂ H 95

Me 2HCl 96

H 97

H 2HCl 98

H 99

H 100

Me 101

H 2HCl 102

H 2HCl 103

H 2HCl 104

H 2HCl 105

H 106

H 107

H HCl 108

H 2HCl 109

H HCl 110 CONH(CH₂)₂NHEt H 111 CONH(CH₂)₂NH₂ H 2HCl 112 CONH(CH₂)₂NHMe HHCl 113

H 114

H 115

H HCl 116

H HCl 117

H 118

H HCl 119

H HCl 120

H 2HCl 121

H 122

H 2HCl 123

H 2HCl 124

H 2HCl 125

H 126

H 127

H 128

H 129

H 2HCl 130

H 131

H 2HCl 132

H 134

H HCl 135

H 2HCl 136

H HCl 137

H 138

H 139

H 140

H 141

H 142

H 2HCl 143

H 144

H 2HCl 145

H 146

H 147

H 148

H 149

H 150

H 151

H 152

H 153

H 154

H 155

H 156

H 157

H 158

H 159

H

Next, pharmacological activities of Compound (I) will be illustratedbelow with reference to the test example.

Test Example

Cytostatic Activity on Leukemia Cell Line and Solid Carcinoma Cell Line

The cytostatic rates of a test compound on human acute myeloid leukemiacell lines MV-4-11 and ML-1, and human chronic myeloid leukemia cellline K562 were determined in the following manner.

Each cell was cultured using Roswell Park Memorial Institute's Medium(RPMI) 1640 (Gibco, Catalog No. 11875-093) containing 10% fetal bovineserum (Gibco, Catalog No. 10437-028) and 1% penicillin/streptomycin(1:1) (Gibco, Catalog No. 15140-122). Each 80 μL of the MV-4-11 cellhaving a concentration of 7.5×10⁴ cells/mL (or the ML-1 cell or K562cell having a concentration of 2.5×10⁴ cells/mL) was inoculated to wellsof a TC MICROWELL 96U plate (Nalge Nunc International, Catalog No.163320) and was cultured in a 5% carbon dioxide gas incubator at 37° C.for 4 hours. As a blank, only RPMI medium (80 μL) was added to a well.Each 20 μL of a solution of the test compound in dimethyl sulfoxide(DMSO) which was prepared to make the final concentration to 10 μmol/L,was added to the MV-4-11 cell, ML-1 cell and K562 cell, respectively.Each 20 μL of DMSO was added to the control well and the blank well to afinal concentration of 0.1%. After adding the test compound, the cellswere incubated in a 5% carbon dioxide gas incubator at 37° C. for 72hours. After adding 20 μL of WST-1 reagent{4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzenedisulfonate sodium salt} (Roche Diagnostics K.K., Catalog No. 1644807)diluted to 50% with RPMI medium, the cells were further incubated at 37°C. for 2 hours. Then, the absorbances at 450 nm (reference wavelength:690 nm) were determined with a microplate spectrophotometer SPECTRA max340PC (Molecular Devices Corporation). The relative growth (%) of a wellto which the test compound had been added was determined while settingthe absorbance of a well to which not the test compound but DMSO alonehad been added (control) at 100% and that of a well containing RPMImedium alone at 0%. The cytostatic rate (%) of the test compound wasdetermined by subtracting the calculated relative growth from 100. Thehigher the cytostatic rate, the stronger the test compound exhibitscytostatic activity on the cell.

The cytostatic rate of a test compound on the human colon cancer cellline Colo205 was determined in the following manner.

The cell was cultured using Roswell Park Memorial Institute's Medium(RPMI) 1640 (Gibco, Catalog No. 11875-093) containing 10% fetal bovineserum (Gibco, Catalog No. 10437-028) and 1% penicillin/streptomycin(1:1) (Gibco, Catalog No. 15140-122). Each 80 μL of the Colo205 having aconcentration of 1.25×10⁴ cells/mL was inoculated to wells of a TCMICROWELL 96F plate (Nalge Nunc International, Catalog No. 167008) andwas cultured in a 5% carbon dioxide gas incubator at 37° C. for 24hours. As a blank, only RPMI (80 μl) was added to a well. Each-20 μL ofa solution of the test compound in DMSO which was prepared to make thefinal concentration to 10 μmol/L, was added to the Colo205 cell. Each 20μL of DMSO was added to the control well and the blank well to a finalconcentration of 0.1%. After adding the test compound, the cell wasincubated in a 5% carbon dioxide gas incubator at 37° C. for 72 hours.The cytostatic rate (%) was then determined in the same way as theleukemia cell lines.

The determined cytostatic rates (%) are shown in Table 2. TABLE 2Compound MV-4-11(%) ML-1(%) K562(%) Colo205(%) Number (10 μmol/L) (10μmol/L) (10 μmol/L) (10 μmol/L) 1 98 93 95 — 7 97 97 98 89 8 95 84 95 —9 91 90 98 — 10 91 83 99 41 13 94 90 99 — 14 76 84 98 — 15 91 94 100 9216 89 97 94 — 18 98 76 91 85 19 97 89 78 89 27 94 77 55 80 32 94 80 8685 40 98 67 96 88 41 97 83 95 90 44 98 85 92 91 46 98 82 93 87 47 97 8888 91 51 98 89 95 90 55 97 83 81 89 56 98 78 87 88 58 96 74 89 85 61 9879 85 87 63 98 87 76 88 64 98 89 91 94 65 97 86 85 88 66 99 74 89 83 6897 79 91 90 72 100 80 95 93 73 97 87 68 89 75 99 88 85 88 77 98 80 95 8678 98 64 90 82 81 98 77 95 85 85 99 78 90 89 86 98 87 88 89 87 99 88 7686 89 98 86 61 92 90 98 79 85 88 92 98 88 89 89 95 96 70 93 86 98 98 7989 88 99 97 86 94 95 101 99 77 92 87 103 100 83 88 89 105 96 85 90 88106 98 58 35 37 107 98 77 91 84 112 98 83 81 88 116 98 79 88 91 122 9879 93 89 124 98 83 94 87 125 98 79 91 86 126 97 87 89 95 128 98 79 87 88131 99 85 98 91 132 100 88 95 91 134 100 88 91 91 135 99 79 93 87 136 9982 94 91 138 99 88 94 91 140 99 82 95 85 143 100 84 95 92 145 99 85 9492 147 99 89 77 83 148 98 81 91 83 150 97 67 90 88 155 97 79 96 88 15699 85 94 92 158 98 80 90 91 159 99 86 93 92

Table 2 shows that Compound (I) exhibit cytostatic activities on thehuman acute myeloid leukemia cell lines MV-4-11 and ML-1, the humanchronic myeloid leukemia cell line K562 and the human colon cancer cellline Colo205.

Compound (I) or pharmaceutically acceptable salt thereof may be used asit is or in various pharmaceutical forms depending upon thepharmacological effect, purpose of administration, etc. A pharmaceuticalcomposition of the present invention can be manufactured by uniformmixing of Compound (I) or a pharmaceutically acceptable salt thereof inan amount which is effective as an active ingredient withpharmaceutically acceptable carriers. These carriers can have forms in awide range according to desired dosage form for administration. It ispreferred that the pharmaceutical composition is in a unit dosage formfor oral administration or parental administration such as injection.

In the manufacture of tablets, excipient such as lactose and mannitol,disintegrator such as starch, lubricant such as magnesium stearate,binder such as polyvinyl alcohol and hydroxypropyl cellulose, andsurfactant such as sucrose fatty acid esters and sorbitol fatty acidesters, etc. may be used in accordance with a conventional procedure.Tablets containing 1 to 200 mg of an active ingredient per tablet arepreferred.

In the manufacture of injections, water, physiological saline, vegetableoil such as olive oil and peanut oil, solvent such as ethyl oleate andpropylene glycol, dissolving agent such as sodium benzoate, sodiumsalicylate and urethane, isotonizing agent such as sodium chloride andglucose, preservative such as phenol, cresol, p-hydroxybenzoate andchlorobutanol, and antioxidant such as ascorbic acid and sodiumpyrosulfite, etc. may be used by a conventional procedure.

Compound (I) or a pharmaceutically acceptable salt thereof can beadministered either orally or parentally by means of injection solution,etc. The effective dose and frequency of administration vary dependingon the dosage form, age, body weight and symptom of a patient, etc. Ingeneral, Compound (I) or a pharmaceutically acceptable salt thereof maypreferably be administered in an amount of 0.01 to 100 mg/kg per day.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be illustrated in further detail withexamples below which by no means limit the scope of the presentinvention.

In proton nuclear magnetic resonance spectra (¹H-NMR) used in theexamples, exchangeable hydrogen may not be clearly observed in somecompounds under some measuring conditions. With regard to indication ofmultiplicity of signals, the commonly used notation is here used,although br means a broad signal as judged by visual inspection.

EXAMPLE 1 (E)-N,N-Dimethyl-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 1)

Step 1

1H-indazole-3-carboxylic acid (45.2 g, 279 mmol) was suspended in THF(500 mL), and to the suspension were added 1-hydroxybenzotriazoledimethylammonium salt (55.7 g, 308 mmol) obtained in a similar manner tothe known method [for example, Synthesis, page 285 (1992)] and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58.9 g, 307mmol), followed by stirring at room temperature overnight. The reactionmixture was added with water, was extracted with ethyl acetate, and theorganic layer was sequentially washed with a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was recrystallized from mixed solvent of acetone/water toobtain N,N-dimethyl-1H-indazole-3-carboxamide (37.7 g, 71%).

¹H-NMR (270 MHz, CDCl₃) δ 3.22 (s, 3H), 3.40 (s, 3H), 7.24 (ddd, J=1.3,6.9, 8.1 Hz, 1H), 7.40 (ddd, J=1.0, 6.9, 8.2 Hz, 1H), 7.48 (dd, J=1.3,8.2 Hz, 1H), 8.15 (dd, J=1.0, 8.1 Hz, 1H), 10.7 (brs, 1H). TOF-MS (m/z);190 [M+1]⁺

Step 2

Lithium aluminum hydride (13.7 g, 36.1 mmol) was suspended in THF (500mL), and the suspension was added with a solution ofN,N-dimethyl-1H-indazole-3-carboxamide obtained in Step 1 (34.2 g, 181mmol) in THF (250 mL), followed by stirring at room temperature underthe flow of nitrogen gas for 30 minutes. The reaction mixture was mixedwith sodium sulfate decahydrate, was stirred for further 1 hour and wasfiltered through Celite. The solvent was evaporated under reducedpressure to obtain 3-dimethylaminomethyl-1H-indazole (24.2 g, 76%).

¹H-NMR (270 MHz, CDCl₃) δ 2.33 (s, 6H), 3.85 (s, 2H), 7.16 (ddd, J=1.3,6.6, 7.9 Hz, 1H), 7.38 (ddd, J=1.0, 6.6, 8.3 Hz, 1H), 7.45 (d, J=8.3 Hz,1H), 7.87 (dd, J=1.0, 7.9 Hz, 1H), 10.0 (brs, 1H).

Step 3

3-Dimethylaminomethyl-1H-indazole (25.6 g, 146 mmol) obtained in Step 2was dissolved in ethyl acetate (350 mL), and the solution was added withmethyl iodide (33.3 mL, 535 mmol), followed by stirring at roomtemperature overnight. The resulting precipitates were collected byfiltration to obtain (1H-indazol-3-ylmethyl)trimethylammonium iodide(45.0 g, 97%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.12 (s, 9H), 4.91 (s, 2H), 7.27 (dd, J=7.3,8.1 Hz, 1H), 7.45 (dd, J=7.3, 8.1 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 8.02(d, J=8.1 Hz, 1H), 13.7 (brs, 1H). TOF-MS (m/z); 190 [M−127]⁺

Step 4

(1H-indazol-3-ylmethyl)trimethylammonium iodide (45.0 g, 142 mmol)obtained in Step 3 was dissolved in DMF (220 mL), and the solution wasmixed with triphenylphosphine (44.7 g, 170 mmol), followed by heatingunder reflux for 2.5 hours. After cooling to room temperature, thereaction mixture was added with diethyl ether and was stirred overnight.The resulting precipitates were collected by filtration to obtain(1H-indazol-3-ylmethyl)triphenylphosphonium iodide (68.3 g, 92%).

¹H-NMR (270 MHz, DMSO-d₆) δ 5.58 (d, J=15.2 Hz, 2H), 6.98 (ddd, J=1.0,7.3, 8.3 Hz, 1H), 7.29 (ddd, J=1.0, 7.3, 8.3 Hz, 1H), 7.43 (d, J=8.3 Hz,1H), 7.57 (d, J=8.3 Hz, 1H), 7.64-7.85 (m, 15H), 13.1 (brs, 1H). TOF-MS(m/z); 393 [M−127]⁺

Step 5

(1H-indazol-3-ylmethyl)triphenylphosphonium iodide (3.20 g, 6.15 mmol)obtained in Step 4 was dissolved in methanol (60 mL), and the solutionwas added with methyl p-formylbenzoate (1.00 g, 6.09 mmol) and potassiumcarbonate (2.55 g, 18.5 mmol), followed by stirring at room temperatureovernight. The reaction mixture was added with water, and was extractedwith ethyl acetate, then the organic layer was washed with saturatedbrine, and was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified bythin-layer chromatography (chloroform/methanol=15/1), was furthertriturated in mixed solvent of ethyl acetate/diisopropyl ether to obtainmethyl (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoate (0.87 g, 51%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.84 (s, 3H), 7.21 (dd, J=7.1, 8.3 Hz, 1H),7.40 (dd, J=7.1, 8.3 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.55 (d, J=16.5Hz, 1H), 7.70 (d, J=16.5 Hz, 1H), 7.84 (d, J=8.1 Hz, 2H), 7.95 (d, J=8.1Hz, 2H), 8.19 (d, J=8.3 Hz, 1H). TOF-MS (m/z); 279 [M+1]⁺

Step 6

Methyl (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoate (0.71 g, 2.54 mmol)obtained in Step 5 was dissolved in methanol (2.6 mL), and thesolution-was added with an aqueous sodium hydroxide solution (1 mol/L,5.00 mL), followed by heating under reflux for 1.5 hours. Methanol wasevaporated under reduced pressure, the pH of the residue was adjusted to3 or below with 6 mol/L hydrochloric acid under ice-cooling. Theresulting precipitates were collected by filtration to obtain(E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.70 g, quantitativeyield).

¹H-NMR (270 MHz, DMSO-d₆) δ 7.21 (dd, J=7.1, 7.9 Hz, 1H), 7.40 (dd,J=7.1, 8.6 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.57 (d, J=16.5 Hz, 1H),7.70 (d, J=16.5 Hz, 1H), 7.83 (d, J=8.3 Hz, 2H), 7.94 (d, J=8.3 Hz, 2H),8.21 (d, J=7.9 Hz, 1H), 13.2 (brs, 1H). TOF-MS (m/z); 265 [M+1]⁺

Step 7

A mixture of a solution of (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acidobtained in Step 6 in THF (0.125 mol/L, 0.40 mL, 0.05 mmol), a solutionof dimethylamine in THF (1 mol/L, 0.08 mL, 0.08 mmol), a solution of1-hydroxybenzotriazole in THF (0.33 mol/L, 0.20 mL, 0.07 mmol) andpolymer-bound 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 mol/g,0.07 g, 0.07 mmol) was shaken at room temperature overnight. Thereaction mixture was filtered, the solvent was evaporated by blowing airto the filtrate, and the residue was added with THF (0.6 mL),polyvinylpyridine (0.03 g, 0.29 mmol) and 4-chloroformyl polystyrene(3.5 mol/g, 0.03 g, 0.11 mmol), followed by shaking at room temperatureovernight. The reaction mixture was filtered, and the solvent wasevaporated by blowing air to the filtrate. The residue was added withethanol (0.5 mL) and ion-exchange resin [Bio-Rad AG (registeredtrademark) 1 X-8 OH form, 0.15 g], followed by shaking for 10 minutes.The mixture was filtered, the resin was washed with ethanol, and theadsorbate was eluted with a 4 mol/L solution of hydrogen chloride inethyl acetate. The solvent was evaporated by blowing air to the eluate,the residue was purified by thin-layer chromatography(chloroform/methanol=9/1) to obtain Compound 1 (0.4 mg, 3%).

TOF-MS (m/z); 292 [M+1]⁺

EXAMPLE 2 (E)-N-(3-Methylbutyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 2)

In a similar manner to Step 7 of Example 1, Compound 2 (1.2 mg, 7%) wasobtained using a solution of (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoicacid obtained in Step 6 of Example 1 in THF (0.125 mol/L, 0.40 mL, 0.05mmol) and a solution of isoamylamine in THF (1 mol/L, 0.08 mL, 0.08mmol).

TOF-MS (m/z); 334 [M+1]⁺

EXAMPLE 3 (E)-N-Benzyl-4-[2-(1H-indazol-3-yl)vinyl]benzamide (Compound3)

In a similar manner to Step 7 of Example 1, Compound 3 (1.3 mg, 7%) wasobtained using a solution of (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoicacid obtained in Step 6 of Example 1 in THF (0.125 mol/L, 0.40 mL, 0.05mmol) and a solution of benzylamine in THF (1 mol/L, 0.08 mL, 0.08mmol).

TOF-MS (m/z); 354 [M+1]⁺

EXAMPLE 4 (E)-N-(2-Methoxyethyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 4)

In a similar manner to Step 7 of Example 1, Compound 4 (0.5 mg, 3%) wasobtained using a solution of (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoicacid obtained in Step 6 of Example 1 in THF (0.125 mol/L, 0.40 mL, 0.05mmol) and a solution of 2-methoxyethylamine in THF (1 mol/L, 0.08 mL,0.08 mmol).

TOF-MS (m/z); 322 [M+1]⁺

EXAMPLE 5(E)-N-(2-Methoxyethyl)-N-methyl-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 5)

(E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.18 g, 0.67 mmol)obtained in Step 6 of Example 1 was dissolved in THF (4 mL), and thesolution was added with N-(2-methoxyethyl)methylamine (0.11 mL, 1.00mmol), 1-hydroxybenzotriazole monohydrate (0.12 g, 0.85 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.18 g,0.92 mmol), followed by stirring at room temperature for 2 hours. Thereaction mixture was added with a saturated aqueous sodiumhydrogencarbonate solution, was extracted with ethyl acetate, theorganic layer was sequentially washed with water and saturated brine,was dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform/methanol=25/1) to obtain Compound5 (0.22 g, 99%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.97 (s, 3H), 3.20 (brm, 2H), 3.31 (s, 3H),3.50 (brm, 2H), 7.20 (dd, J=7.3, 7.9 Hz, 1H), 7.39 (m, 1H), 7.40 (d,J=8.2 Hz, 2H), 7.54 (d, J=16.7 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.60 (d,J=16.7 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H), 8.19 (d, J=7.9 Hz, 1H), 13.2(brs, 1H). TOF-MS (m/z); 336 [M+1]⁺

EXAMPLE 6(E)-N-(2-Dimethylaminoethyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 6)

In a similar manner to Example 5, Compound 6 (0.06 g, 42%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.12 g, 0.40 mmol)obtained in Step 6 of Example 1, N,N-dimethylethylenediamine (0.07 mL,0.60 mmol), 1-hydroxybenzotriazole monohydrate (0.07 g, 0.52 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g,0.57 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.18 (s, 6H), 2.40 (t, J=6.6 Hz, 2H), 3.31(m, 2H), 7.21 (dd, J=7.3, 7.9 Hz, 1H), 7.39 (dd, J=7.3, 7.9 Hz, 1H),7.55 (d, J=7.9 Hz, 1H), 7.56 (d, J=16.8 Hz, 1H), 7.65 (d, J=16.8 Hz,1H), 7.79 (d, J=8.3 Hz, 2H), 7.85 (d, J=8.3 Hz, 2H), 8.20 (d, J=7.9 Hz,1H), 8.38 (brm, 1H), 13.2 (brs, 1H). TOF-MS (m/z); 335 [M+1]⁺

EXAMPLE 7(E)-N-{5-[2-(1H-Indazol-3-yl)vinyl]-2-(2-morpholinoethoxy)phenyl}methanesulfonamide(Compound 7)

Step 1

A solution of 4-hydroxy-3-nitrobenzaldehyde (6.37 g, 38.1 mmol) in DMF(10.0 mL) was added with potassium carbonate (15.8 g, 114 mmol) and2-(N-morpholino)ethyl chloride hydrochloride (7.09 g, 38.1 mmol),followed by stirring at 80° C. for 7 hours. After cooling to roomtemperature, the reaction mixture was added with water (40 mL), wasextracted with ethyl acetate (100 mL×4), the organic layer was driedover anhydrous sodium sulfate, was treated with a 4 mol/L solution ofhydrogen chloride in ethyl acetate to obtain4-(2-morpholinoethoxy)-3-nitrobenzaldehyde hydrochloride (6.07 g, 50%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.24-4.00 (m, 10H), 4.78 (t, J=4.7 Hz, 2H),7.62 (d, J=8.8 Hz, 1H), 8.22 (dd, J=2.0, 8.8 Hz, 1H), 8.48 (d, J=2.0 Hz,1H), 9.97 (s, 1H), 11.6 (brs, 1H). APCI-MS (m/z); 281 [M+H]⁺

Step 2

A solution of 4-(2-morpholinoethoxy)-3-nitrobenzaldehyde hydrochlorideobtained in Step 1 (2.97 g, 9.38 mmol) in dichloromethane (10.0 mL) wasadded with trimethyl orthoformate (15.0 mL, 13.7 mmol) and a 10%solution of hydrogen chloride in methanol (5.00 mL), followed bystirring at room temperature for 4 hours. The reaction mixture was addedwith potassium carbonate (10.0 g, 72.4 mmol), then stirred at roomtemperature for 5 hours, and the solvent was evaporated under reducedpressure. The residue was added with water (50 mL) and was extractedwith ethyl acetate (50 mL×3). After drying over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure to obtain4-dimethoxymethyl-1-(2-morpholinoethoxy)-2-nitrobenzene (2.98 g, 97%).

¹H-NMR (300 MHz, CDCl₃) δ 2.60 (brt, J=4.7 Hz, 4H), 2.85 (t, J=5.6 Hz,2H), 3.32 (s, 6H), 3.71 (brt, J=4.7 Hz, 4H), 4.25 (t, J=5.6 Hz, 2H),5.39 (s, 1H), 7.07 (d, J=8.6 Hz, 1H), 7.59 (dd, J=2.2, 8.6 Hz, 1H), 7.93(d, J=2.2 Hz, 1H). ESI-MS (m/z); 327 [M+H]⁺

Step 3

A solution of 4-dimethoxymethyl-1-(2-morpholinoethoxy)-2-nitrobenzeneobtained in Step 2 (2.97 g, 9.10 mmol) in ethanol (30.0 mL) was addedwith platinum oxide (0.02 g, 0.10 mmol), followed by stirring at roomtemperature under hydrogen atmosphere for 2 hours. The reaction mixturewas filtered, the solvent of filtrate was evaporated under reducedpressure, the resulting crude product was crystallized from mixedsolvent of ethyl acetate/hexane (1/1) to obtain5-dimethoxymethyl-2-(2-morpholinoethoxy)aniline (0.70 g, 26%).

¹H-NMR (300 MHz, CDCl₃) δ 2.57 (brt, J=4.7 Hz, 4H), 2.78 (t, J=5.7 Hz,2H), 3.30 (s, 6H), 3.72 (brt, J=4.7 Hz, 4H), 3.91 (brs, 2H), 4.12 (t,J=5.7 Hz, 2H), 5.25 (s, 1H), 6.76-6.81 (m, 3H). ESI-MS (m/z); 297 [M+H]⁺

Step 4

A solution of 5-dimethoxymethyl-2-(2-morpholinoethoxy)aniline obtainedin Step 3 (0.27 g, 0.91 mmol) in dichloromethane (2.00 mL) was addedwith methanesulfonyl chloride (0.11 mL, 1.42 mmol) and pyridine (0.50mL, 6.18 mmol), followed by stirring at room temperature for 10 hours.The reaction mixture was added with hydrochloric acid (3 mol/L, 3.00mL), was stirred at room temperature for 20 minutes, was neutralizedwith a saturated aqueous sodium hydrogencarbonate solution (50 ml) andwas extracted with ethyl acetate (50 mL×3). The organic layer was driedover anhydrous sodium sulfate, the solvent was evaporated under reducedpressure. the crude product was purified by silica gel columnchromatography (chloroform, then methanol/chloroform=1/6) to obtain3-methanesulfonylamino-4-(2-morpholinoethoxy)benzaldehyde (0.28 g, 95%).

¹H-NMR (300 MHz, CDCl₃) δ 2.56 (brt, J=4.6 Hz, 4H), 2.70 (t, J=5.5 Hz,2H), 2.99 (s, 3H), 3.80 (brt, J=4.6 Hz, 4H), 4.28 (t, J=5.5 Hz, 2H),7.14 (d, J=8.4 Hz, 1H), 7.71 (dd, J=2.0, 8.4 Hz, 1H), 8.03 (d, J=2.0 Hz,1H), 9.91 (s, 1H). ESI-MS (m/z); 327 [M−H]⁻

Step 5

A solution of 3-methanesulfonylamino-4-(2-morpholinoethoxy)benzaldehydeobtained in Step 4 (0.27 g, 0.83 mmol) in DMF (5.0 mL) was added with(1H-indazol-3-ylmethyl)triphenylphosphonium iodide obtained in Step 4 ofExample 1 (0.40 g, 0.77 mmol) and potassium carbonate (0.23 g, 1.66mmol), followed by stirring at room temperature for 2 hours, and furtherstirring at 60° C. for 11 hours. After cooling to room temperature, thesolvent was evaporated under reduced pressure, the crude product waspurified by silica gel chromatography [amino-modified chemically boundsilica gel Chromatorex (registered trademark) NH, Fuji Silysia ChemicalLtd.; ethyl acetate, then methanol/ethyl acetate=1/19], was crystallizedfrom ethyl acetate to obtain Compound 7 (0.05 g, 14%).

¹H-NMR (300 MHz, CDCl₃) δ 2.58-2.61 (m, 6H), 2.94 (s, 3H), 3.87 (brt,J=4.7 Hz, 4H), 4.23 (t, J=5.6 Hz, 2H), 7.07 (d, J=8.4 Hz, 1H), 7.23-7.29(m, 1H), 7.39 (d, J=16.5 Hz, 1H), 7.48 (d, J=16.5 Hz, 1H), 7.40-7.51 (m,3H), 7.77 (d, J=2.2 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H). ESI-MS (m/z); 443[M+H]⁺

EXAMPLE 8(E)-5-[2-(1H-Indazol-3-yl)vinyl]-2-(2-morpholinoethoxy)benzamide(Compound 8)

Step 1

A solution of 4-hydroxybenzaldehyde (10.0 g, 81.9 mmol) in chloroform(100 mL) was added with bromine (4.30 mL, 83.5 mmol), followed bystirring at room temperature for 2 hours. The reaction mixture was addedwith water (100 mL), and the solvent of the organic layer was evaporatedunder reduced pressure to obtain 3-bromo-4-hydroxybenzaldehyde as a paleyellow solid (quantitative yield).

¹H-NMR (270 MHz, CDCl₃) δ 6.27 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.78(dd, J=1.9, 8.4 Hz, 1H), 8.04 (d, J=1.9 Hz, 1H), 9.83 (s, 1H). ESI-MS(m/z); 199, 201 [M−H]⁻

Step 2

In a similar manner to Step 1 of Example 7,3-bromo-4-(2-morpholinoethoxy)benzaldehyde hydrochloride (10.9 g, 49%)was obtained using 3-bromo-4-hydroxybenzaldehyde obtained in Step 1(14.3 g, 71.0 mmol), potassium carbonate (20.0 g, 145 mmol) and2-(N-morpholino)ethyl chloride hydrochloride (13.5 g, 72.6 mmol).

¹H-NMR (270 MHz, CDCl₃) δ 2.65 (brt, J=4.7 Hz, 4H), 2.91 (t, J=5.6 Hz,2H), 3.73 (brt, J=4.7 Hz, 4H), 4.26 (t, J=5.6 Hz, 2H), 7.00 (d, J=8.4Hz, 1H), 7.80 (dd, J=2.0, 8.4 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 9.84 (s,1H). ESI-MS (m/z); 314, 316 [M+H]⁺

Step 3

In a similar manner to Step 2 of Example 7,1-bromo-5-dimethoxymethyl-2-(2-morpholinoethoxy)benzene (4.57 g, 98%)was obtained using 3-bromo-4-(2-morpholinoethoxy)benzaldehydehydrochloride obtained in Step 2 (4.08 g, 13.0 mmol), trimethylorthoformate (20.0 mL, 18.3 mmol) and a 10% solution of hydrogenchloride in methanol (10 mL).

¹H-NMR (300 MHz, CDCl₃) δ 2.60 (brt, J=4.7 Hz, 4H), 2.85 (t, J=5.6 Hz,2H), 3.32 (s, 6H), 3.71 (brt, J=4.7 Hz, 4H), 4.25 (t, J=5.6 Hz, 2H),5.39 (s, 1H), 7.07 (d, J=8.6 Hz, 1H), 7.59 (dd, J=2.2, 8.6 Hz, 1H), 7.93(d, J=2.2 Hz, 1H). ESI-MS (m/z); 327 [M+H]⁺

Step 4

A solution of 1-bromo-5-dimethoxymethyl-2-(2-morpholinoethoxy)benzene(3.11 g, 8.63 mmol) obtained in Step 3 in THF (40.0 mL) was cooled to−78° C., to which n-butyllithium (1.60 mol/L, 20.0 mL, 32.0 mmol) wasadded dropwise for 3 minutes, followed by stirring at −78° C. for 5minutes. The reaction mixture was added with dry ice and was stirred for3 hours while warming to room temperature. The solvent of the reactionmixture was evaporated under reduced pressure. The residue was addedwith a 1 mol/L aqueous ammonium acetate solution (30 mL), was purifiedby HP-20 column chromatography (water, then acetonitrile/water=2/1),then crystallized from mixed solvent of ethyl acetate/hexane (1/1) toobtain 5-dimethoxymethyl-2-(2-morpholinoethoxy)benzoic acid (0.58 g,21%).

¹H-NMR (300 MHz, CD₃OD) δ 2.64 (brt, J=4.8 Hz, 4H), 2.83 (t, J=5.6 Hz,2H), 3.28 (s, 6H), 3.70 (brt, J=4.8 Hz, 4H), 4.19 (t, J=5.6 Hz, 2H),5.31 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.29 (dd, J=2.2, 8.4 Hz, 1H), 7.43(d, J=2.2 Hz, 1H). ESI-MS (m/z); 362 [M+H]⁺

Step 5

A solution of 5-dimethoxymethyl-2-(2-morpholinoethoxy)benzoic acid (0.40g, 1.23 mmol) obtained in Step 4 in DMF (5.00 mL) was added with1-hydroxybenzotriazole ammonium salt (0.30 g, 1.97 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 g,1.84 mmol), followed by stirring at room temperature for 35 hours. Thesolvent of the reaction mixture was evaporated under reduced pressure,and the residue was added with hydrochloric acid (3 mol/L, 3.00 mL),followed by stirring at room temperature for 1 hour. The reactionmixture was neutralized with a saturated aqueous sodiumhydrogencarbonate solution (50 mL) and was extracted with ethyl acetate(50 mL×3). After drying over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure to obtain5-formyl-2-(2-morpholinoethoxy)benzamide (0.25 g, 73%).

¹H-NMR (300-MHz, CDCl₃) δ 2.55 (brt, J=4.7 Hz, 4H), 2.87 (t, J=5.4 Hz,2H), 3.71 (brt, J=4.7 Hz, 4H), 4.32 (t, J=5.4 Hz, 2H), 5.80 (brs, 1H),7.10 (d, J=8.6 Hz, 1H), 8.04 (dd, J=2.2, 8.6 Hz, 1H), 8.50 (brs, 1H),8.71 (d, J=2.2 Hz, 1H), 9.98 (s, 1H). ESI-MS (m/z); 279 [M+H]⁺

Step 6

In a similar manner to Step 5 of Example 7, Compound 8 (0.13 g, 46%) wasobtained using 5-formyl-2-(2-morpholinoethoxy)benzamide (0.20 g, 0.72mmol) obtained in Step 5, (1H-indazol-3-ylmethyl)triphenylphosphoniumiodide (0.38 g, 0.72 mmol) obtained in Step 4 of Example 1 and potassiumcarbonate (0.20 g, 1.45 mmol).

¹H-NMR (300 MHz, CDCl₃) δ 2.55 (brt, J=4.6 Hz, 4H), 2.84 (t, J=5.4 Hz,2H), 3.71 (brt, J=4.6 Hz, 4H), 4.27 (t, J=5.4 Hz, 2H), 5.71 (brs, 1H),7.00 (d, J=8.6 Hz, 1H), 7.23-7.28 (m, 1H), 7.40-7.51 (m, 2H), 7.44 (d,J=16.5 Hz, 1H), 7.53 (d, J=16.5 Hz, 1H), 7.69 (dd, J=2.4, 8.6 Hz, 1H),8.04 (d, J=8.1 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.62 (brs, 1H), 10.1(brs, 1H). ESI-MS (m/z); 393 [M+H]⁺

EXAMPLE 9 (E)-1-{4-[2-(1H-indazol-3-yl)vinyl]}benzoylmorpholine(Compound 9)

In a similar manner to Example 5, Compound 9 (2.65 g, 84%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (2.50 g, 9.47 mmol)obtained in Step 6 of Example 1, morpholine (1.24 mL, 14.2 mmol),1-hydroxybenzotriazole monohydrate (1.70 g, 11.2 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.54 g,13.3 mmol).

¹H-NMR (270 MHz, CDCl₃) δ 3.50-3.80 (brm, 8H), 6.91 (d, J=3.3 Hz, 1H),7.45-7.54 (m, 6H), 7.66 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 10.2(br, 1H). ESI-MS (m/z); 334 [M+H]⁺

EXAMPLE 10(E)-N-(2-morpholinoethyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 10)

In a similar manner to Example 5, Compound 10 (0.24 g, 55%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.30 g, 1.14 mmol)obtained in Step 6 of Example 1, 2-morpholinoethylamine (0.22 mL, 1.71mmol), 1-hydroxybenzotriazole monohydrate (0.20 g, 1.31 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.31 g,1.62 mmol).

¹H-NMR (270 MHz, CDCl₃) δ 2.54 (brt, J=4.6 Hz, 4H), 2.64 (t, J=6.0 Hz,2H), 3.59 (q, J=5.5 Hz, 2H), 3.76 (brt, J=4.8 Hz, 4H), 6.92 (brm, 1H),7.26 (t, J=6.6 Hz, 1H), 7.43 (t, J=7.3 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H),7.63 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.1 Hz, 1H).ESI-MS (m/z); 377 [M+H]⁺

EXAMPLE 11(E)-N-[2-(acetylamino)ethyl]-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 11)

In a similar manner to Example 5, Compound 11 (0.30 g, 64%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.35 g, 1.33 mmol)obtained in Step 6 of Example 1, N-acetylethylenediamine (0.41 mL, 4.01mmol), 1-hydroxybenzotriazole monohydrate (0.23 g, 1.51 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g,1.62 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.81 (s, 3H), 3.19-3.31 (m, 4H), 7.21 (t,J=7.5 Hz, 1H), 7.39 (t, J=7.3 Hz, 1H), 7.52-7.88 (m, 4H), 7.98 (brm,1H), 8.20 (d, J=8.1 Hz, 1H), 8.51 (brt, J=8.1 Hz, 1H), 13.3 (brs, 1H).ESI-MS (m/z); 349 [M+H]⁺

EXAMPLE 12(E)-N-methyl-5-[2-(1H-indazol-3-yl)vinyl]-2-(2-morpholinoethoxy)benzamide(Compound 12)

Step 1

In a similar manner to Example 5,N-methyl-5-dimethoxymethyl-2-(2-morpholinoethyl)benzamide (0.16 g, 94%)was obtained using 5-dimethoxymethyl-2-(2-morpholinoethoxy)benzoic acid(0.19 g, 0.59 mmol) obtained in Step 4 of Example 8, methylaminehydrochloride (0.08 g, 1.18 mmol), 1-hydroxybenzotriazole monohydrate(0.13 g, 0.85 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.18 g, 1.17 mmol).

¹H-NMR (300 MHz, CDCl₃) δ 2.56 (brt, J=4.6 Hz, 4H), 2.88 (t, J=5.4 Hz,2H), 3.05 (d, J=4.8 Hz, 3H), 3.75 (brt, J=4.6 Hz, 4H), 4.32 (t, J=5.4Hz, 2H), 7.07 (d, J=8.6 Hz, 1H), 7.99 (dd, J=2.2, 8.6 Hz, 1H), 8.43(brs, 1H), 8.71 (d, J=2.2 Hz, 1H), 9.97 (s, 1H). APCI-MS (m/z); 293[M+H]⁺

Step 2

In a similar manner to Step 5 of Example 7, Compound 12 (0.06 g, 25%)was obtained usingN-methyl-5-dimethoxymethyl-2-(2-morpholinoethyl)benzamide (0.16 g, 0.54mmol) obtained in Step 1, (1H-indazol-3-ylmethyl)triphenylphosphoniumiodide (0.13 g, 0.85 mmol) obtained in Step 4 of Example 1 and potassiumcarbonate (0.08 g, 1.18 mmol).

¹H-NMR (270 MHz, CDCl₃) δ 2.56 (brt, J=4.6 Hz, 4H), 2.85 (t, J=5.4 Hz,2H), 3.07 (d, J=4.8 Hz, 3H), 3.76 (brt, J=4.6 Hz, 4H), 4.26 (t, J=5.4Hz, 2H), 6.98 (d, J=8.6 Hz, 1H), 7.23-7.29 (m, 1H), 7.42 (d, J=16.5 Hz,1H), 7.43-7.50 (m, 2H), 7.53 (d, J=16.5 Hz, 1H), 7.65 (dd, J=2.3, 8.6Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 8.46 (d, J=2.3 Hz, 1H), 8.53 (brs, 1H),9.99 (brs, 1H). APCI-MS (m/z); 407 [M+H]⁺

EXAMPLE 13(E)-4-Acetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine (Compound13)

In a similar manner to Example 5, Compound 13 (0.69 g, 98%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.50 g, 1.89 mmol)obtained in Step 6 of Example 1, 4-acetylpiperazine (0.73 g, 5.67 mmol),1-hydroxybenzotriazole monohydrate (0.33 g, 2.17 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.51 g,2.66 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.81 (s, 3H), 3.42-3.63 (brm, 8H), 7.22 (t,J=7.2 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.52-7.68(m, 3H), 7.80 (d, J=8.2 Hz, 2H), 8.21 (d, J=8.2 Hz, 1H), 13.2 (brs, 1H).ESI-MS (m/z); 375 [M+H]⁺

EXAMPLE 14 (E)-N-Methyl-4-[2-(1H-indazol-3-yl)vinyl]benzamide (Compound14)

In a similar manner to Example 5, Compound 14 (0.12 g, 55%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.20 g, 0.76 mmol)obtained in Step 6 of Example 1, methylamine hydrochloride (0.08 g, 1.19mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.20 g, 1.06 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.79 (d, J=4.4 Hz, 3H), 7.21 (t, J=7.2 Hz,1H), 7.40 (t, J=7.2 Hz, 1H), 7.50-7.88 (m, 7H), 8.20 (d, J=8.1 Hz, 1H),8.42 (brm, 1H), 13.2 (br, 1H). ESI-MS (m/z); 278 [M+H]⁺

EXAMPLE 15 (E)-N,N-Diethyl-4-[2-(1H-indazol-3-yl)vinyl]benzamidehydrochloride (Compound 15)

In a similar manner to Example 5, a free base of Compound 15 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.50 g,1.89 mmol) obtained in Step 6 of Example 1, diethylamine (0.29 mL, 2.80mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.51 g, 2.67 mmol). Then, the free base of Compound 15 was dissolved inacetic acid (5 mL) and was added with a 4 mol/L solution of hydrogenchloride in ethyl acetate (1.00 mL), followed by stirring at roomtemperature for 30 minutes. The resulting precipitates were collected byfiltration to obtain Compound 15 (0.11 g, 18%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.10 (brm, 6H), 3.27-3.37 (brm, 4H), 7.21(t, J=7.9 Hz, 1H), 7.35 (d, J=8.1 Hz, 2H), 7.38 (t, J=6.9 Hz, 1H),7.49-7.64 (m, .3H), 7.75 (d, J=8.2 Hz, 2H), 8.19 (d, J=8.2 Hz, 1H), 10.9(br, 1H). ESI-MS (m/z); 320 [M+H]⁺

EXAMPLE 16(E)-4-ethylenedioxy-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperidinehydrochloride (Compound 16)

In a similar manner to Example 5, a free base of Compound 16 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.50 g,1.89 mmol) obtained in Step 6 of Example 1,1,4-dioxa-8-azaspiro[4.5]decane (0.36 mL, 2.81 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.51 g,2.67 mmol), and then the free base of Compound 16 was treated with 4mol/L hydrogen chloride-ethyl acetate solution to obtain Compound 16(0.56 g, 76%) in a similar manner to Example 15.

¹H-NMR (270 MHz, DMSO-d₆) δ 1.61-1.71 (brm, 4H), 4.17-4.39 (brm, 8H),7.20 (t, J=8.1 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H),7.47-7.64 (m, 3H), 7.76 (d, J=8.2 Hz, 2H), 8.19 (d, J=8.2 Hz, 1H), 11.0(br, 1H). ESI-MS (m/z); 390 [M+H]⁺

EXAMPLE 17(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine-1-carboxylic acid1,1-dimethylethylester (Compound 17)

In a similar manner to Example 5, Compound 17 (0.27 g, 33%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.50 g, 1.89 mmol)obtained in Step 6 of Example 1, 4-(tert-butoxycarbonyl)piperazine (0.53g, 2.84 mmol), 1-hydroxybenzotriazole monohydrate (0.33 g, 2.17 mmol)and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.51 g,2.66 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.41 (s, 9H), 3.23-3.57 (brm, 8H), 7.20 (t,J=7.2 Hz, 1H), 7.39 (t, J=7.2 Hz, 1H), 7.42 (d, J=8.3 Hz, 2H), 7.53 (d,J=16.7 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.63 (d, J=16.7 Hz, 1H), 7.78(d, J=8.2 Hz, 2H), 8.19 (d, J=8.2 Hz, 1H), 13.2 (brs, 1H). ESI-MS (m/z);431 [M−H]⁻

EXAMPLE 18 (E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 18)

Step 1

To the solution of Compound 17 (0.27 g, 0.62 mmol) in methanol (2 mL),10% hydrogen chloride-methanol solution (2 mL) was added, followed bystirring at 60° C. for 30 minutes. After cooling to room temperature,methanol was evaporated to obtain dihydrochloride of Compound 18 (0.21g, 74%).

Step 2

Dihydrochloride of Compound 18 (0.10 g) obtained in Step 1 was addedwith chloroform (20 mL) and saturated aqueous sodium hydrogencarbonatesolution (20 mL), followed by stirring at room temperature for 1 hour,then the reaction mixture was extracted with chloroform. The organiclayer was washed with saturated brine and dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Afterthe residue was recrystallized from ethyl acetate, the obtained crystalwas washed with mixed solvent of ethyl acetate/hexane (1:1) to obtainCompound 18 (0.022 g, 27%).

¹H-NMR (270 MHz, CDCl₃) δ 2.78-3.02 (m, 4H), 3.32-3.89 (m, 4H),7.20-7.52 (m, 7H), 7.60 (d, J=8.4 Hz, 2H), 8.03 (d, J=8.1 Hz, 1H), 10.8(brs, 1H). APCI-MS (m/z); 333 [M+H]⁺

EXAMPLE 19(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine-1-carbaldehyde(Compound 19)

In a similar manner to Example 5, Compound 19 (0.34 g, 99%) was obtainedusing Compound 18 (0.40 g, 0.95 mmol), formic acid (0.03 mL),1-hydroxybenzotriazole monohydrate (0.27 g, 1.96 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g,0.90 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.45-3.57 (brm, 8H), 7.21 (t, J=7.2 Hz, 1H),7.40 (t, J=7.2 Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.53 (d, J=16.6 Hz, 1H),7.54 (d, J=8.2 Hz, 1H), 7.64 (d, J=16.6 Hz, 1H), 7.79 (d, J=8.2 Hz, 2H),8.06 (s, 1H), 8.20 (d, J=8.2 Hz, 1H), 13.2 (brs, 1H). ESI-MS (m/z); 361[M+H]⁺

EXAMPLE 20(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-methylpiperidine (Compound20)

In a similar manner to Example 5, Compound 20 (160 mg, 25%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.50 g, 1.89 mmol)obtained in Step 6 of Example 1, 4-methylpiperidine (0.34 mL, 2.84mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510mg, 2.67 mmol) and N-methylmorpholine (0.41 mL, 3.73 mmol).

¹H-NMR (270 MHz, CDCl₃) δ 0.92 (d, J=6.3 Hz, 3H), 1.02-1.16 (m, 2H),1.58-1.64 (m, 3H), 2.82-2.94 (brm, 4H), 7.20 (dt, J=7.9, 0.8 Hz, 1H),7.36-7.42 (m, 3H), 7.49-7.54 (m, 2H), 7.61 (d, J=17.0 Hz, 1H), 7.76(brd, J=8.3 Hz, 2H), 8.19 (d, J=8.6 Hz, 1H), 13.2 (br, 1H). ESI-MS(m/z); 346 [M+H]⁺

EXAMPLE 21(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-methylpiperazine (Compound21)

In a similar manner to Example 5, Compound 21 (230 mg, 35%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.50 g, 1.89 mmol)obtained in Step 6 of Example 1, N-methylpiperazine (0.315 mL, 2.84mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510mg, 2.67 mmol) and N-methylmorpholine (0.41 mL, 3.73 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.20 (s, 3H), 2.32-2.40 (m, 4H), 3.47-3.53(m, 4H), 7.21 (dt, J=7.3, 0.8 Hz, 1H), 7.38-7.45 (m, 3H), 7.50-7.66 (m,2H), 7.68 (d, J=16.8 Hz, 1H), 7.77 (brd, J=8.1 Hz, 2H), 8.19 (d, J=8.4Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 347 [M+H]⁺

EXAMPLE 22(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(2-pyrimidinyl)piperazine(Compound 22)

In a similar manner to Example 5, Compound 22 (56.0 mg, 7%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.50 g, 1.89 mmol)obtained in Step 6 of Example 1, N-(2-pyrimidinyl)piperazine (674 mg,2.84 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(510 mg, 2.67 mmol) and N-methylmorpholine (0.41 mL, 3.73 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.45-3.56 (brm, 4H), 3.75-3.84 (brm, 4H),6.66 (t, J=7.8 Hz, 1H), 7.21 (dt, J=7.9, 0.8 Hz, 1H), 7.40 (dt, J=7.3,0.8 Hz, 1H), 7.45-7.57 (m, 4H), 7.66 (d, J=16.7 Hz, 1H), 7.79 (brd,J=8.0 Hz, 2H), 8.20 (d, J=8.2 Hz, 1H), 8.38 (d, J=8.4 Hz, 2H), 13.2(brs, 1H). ESI-MS (m/z); 411 [M+H]⁺

EXAMPLE 23(E)-4-(2-furoyl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 23)

In a similar manner to Example 5, Compound 23 (436 mg, 53%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in Step 6 of Example 1, N-(2-furoyl)piperazine (512 mg, 2.84mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510mg, 2.67 mmol) and N-methylmorpholine (0.42 mL, 3.82 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.48-3.81 (brm, 8H), 6.63 (m, 1H), 7.02 (d,J=3.5 Hz, 1H), 7.21 (t, J=7.4 Hz, 1H), 7.39 (t, J=7.1 Hz, 1H), 7.49-7.68(m, 4H), 7.78-7.84 (m, 3H), 8.20 (d, J=8.1 Hz, 2H), 13.2 (brs, 1H).ESI-MS (m/z); 427 [M+H]⁺

EXAMPLE 24(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-phenyl-1,2,3,6-tetrahydropyridine(Compound 24)

In a similar manner to Example 5, Compound 24 (98.9 mg, 12%) wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.50 g,1.89 mmol) obtained in Step 6 of Example 1,4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (555 mg, 2.84 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.66 mmol) and N-methylmorpholine (0.42 mL, 3.82 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.57 (br, 2H), 3.30 (br, 2H), 4.01-4.03 (m,2H), 7.23 (t, J=7.6 Hz, 1H), 7.24-7.58 (m, 10H), 7.64 (d, J=16.6 Hz,1H), 7.80 (d, J=8.1 Hz, 2H), 8.20 (d, J=8.1 Hz, 1H), 13.2 (br, 1H).ESI-MS (m/z); 406 [M+H]⁺

EXAMPLE 25(E)-N-[2-(2-pyridyl)ethyl]-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 25)

In a similar manner to Example 5, Compound 25 (238 mg, 34%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in Step 6 of Example 1, 2-(2-aminoethyl)pyridine (0.34 mL, 2.84mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510mg, 2.67 mmol) and N-methylmorpholine (0.42 mL, 3.82 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.01 (t, J=7.2 Hz, 2H), 3.62 (q, J=6.8 Hz,2H), 7.18-7.30 (m, 3H), 7.40 (t, J=7.1 Hz, 1H), 7.51-7.86 (m, 8H), 8.19(d, J=8.2 Hz, 1H), 8.50 (brd, J=4.0 Hz, 1H), 8.57 (brt, J=5.5 Hz, 1H),13.2 (br, 1H). ESI-MS (m/z); 369 [M+H]⁺

EXAMPLE 26(E)-4-[2-(1H-indazol-3-yl)vinyl]-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzamidehydrochloride (Compound 26)

In a similar manner to Example 5, a free base of Compound 26 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg,1.89 mmol) obtained in Step 6 of Example 1,1-(3-aminopropyl)-2-pyrrolidinone (0.27 mL, 1.93 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.67 mmol) and N-methylmorpholine (0.42 mL, 3.82 mmol), then the freebase of Compound 26 was dissolved in acetic acid (5.00 mL), and wasadded with 4 mol/L hydrogen chloride-ethyl acetate solution (1.00 mL),followed by stirring at room temperature for 30 minutes. The precipitatein the reaction mixture was filtered to obtain Compound 26 (124 mg,15%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.70 (quin, J=6.9 Hz, 2H), 1.93 (quin, J=7.6Hz, 2H), 2.22 (t, J=8.1 Hz, 2H), 3.23 (brt, J=7.0 Hz, 4H), 3.35 (t,J=7.0 Hz, 2H), 7.21 (dt, J=7.9, 0.8 Hz, 1H), 7.39 (dt, J=8.2, 1.3 Hz,1H), 7.51-7.57 (m, 3H), 7.67 (d, J=16.7 Hz, 1H), 7.71-7.88 (m, 4H), 8.19(d, J=8.1 Hz, 1H), 8.50 (br, 1H). ESI-MS (m/z); 389 [M+H]⁺

EXAMPLE 27 (E)-N-{3-[2-(1H-indazol-3-yl)vinyl]phenyl}methanesulfonamide(Compound 27)

In a similar manner to Step 5 of Example 1, Compound 27 (50.0 mg, 6%)was obtained using (1H-indazol-3-ylmethyl)triphenylphosphonium iodide(880 mg, 3.01 mmol), N-(3-formylphenyl)methanesulfonamide (880 mg, 3.01mmol) and potassium carbonate (694 mg, 5.02 mmol).

¹H-NMR (270 MHz, CDCl₃) δ 7.17 (d, J=2.0 Hz, 1H), 7.25-7.30 (m, 1H),7.42-7.53 (m, 9H), 8.03 (d, J=8.1 Hz, 1H). APCI-MS (m/z); 314 [M+H]⁺

EXAMPLE 28 (E)-N-{3-[2-(1H-indazol-3-yl)vinyl]phenyl}benzenesulfonamidehydrochloride (Compound 28)

In a similar manner to Step 5 of Example 1, a free base of Compound 28was obtained using (1H-indazol-3-ylmethyl)triphenylphosphonium iodide(672 mg, 2.3 mmol), N-(3-formylphenyl)benzenesulfonamide (500 mg, 1.91mmol) and potassium carbonate (528 mg, 3.82 mmol), and then the freebase of Compound 28 was treated with 4 mol/L hydrogen chloride-ethylacetate solution to obtain Compound 28 (85.3 mg, 12%) in a similarmanner to Example 15.

¹H-NMR (270 MHz, CDCl₃) δ 6.85-7.10 (m, 2H), 7.25 (d, J=2.4 Hz, 1H),7.36-7.55 (m, 7H), 7.23-7.64 (m, 4H), 7.84-7.90 (m, 2H), 8.03 (d, J=8.1Hz, 1H). APCI-MS (m/z); 376 [M+H]⁺

EXAMPLE 29(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(ethoxycarbonylmethyl)piperazine(Compound 29)

In a similar manner to Example 5, Compound 29 (86.7 mg, 11%) wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg,1.89 mmol) obtained in Step 6 of Example 1,1-(ethoxycarbonylmethyl)piperazine (490 mg, 2.84 mmol),1-hydroxybenzotriazole monohydrate (332 mg, 2.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.67 mmol) and N-methylmorpholine (0.42 mL, 3.82 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.18 (t, J=7.2 Hz, 3H), 2.48-2.55 (m, 4H),3.30 (s, 2H), 3.51-3.68 (m, 4H), 4.08 (q, J=7.2 Hz, 2H), 6.81 (d, J=12.9Hz, 1H), 6.92-6.99 (m, 2H), 7.24-7.33 (m, 4H), 7.50 (d, J=7.9 Hz, 1H),7.66 (brd, J=8.2 Hz, 2H), 13.2 (br, 1H). APCI-MS (m/z); 419 [M+H]⁺

EXAMPLE 30(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(2-morpholino-2-oxoethyl]piperazine(Compound 30)

In a similar manner to Example 5, Compound 30 (363 mg, 42%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in Step 6 of Example 1, 1-(ethoxycarbonylmethyl)piperazine (606mg, 2.84 mmol), 1-hydroxybenzotriazole monohydrate (332 mg, 2.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.67 mmol) and N-methylmorpholine (0.42 mL, 3.82 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.49-2.54 (m, 4H), 3.21 (s, 2H), 3.35-3.58(m, 10H), 7.21 (t, J=7.1 Hz, 1H), 7.35-7.43 (m, 3H), 7.50-7.66 (m, 4H),7.76 (d, J=8.1 Hz, 2H), 8.19 (brd, J=8.1 Hz, 2H), 13.2 (br, 1H). APCI-MS(m/z); 460 [M+H]⁺

EXAMPLE 31(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(benzo[1,3]dioxol-5-yl)methylpiperazine(Compound 31)

In a similar manner to Example 5, Compound 31 (246 mg, 28%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic-acid (0.50 g, 1.89 mmol)obtained in Step 6 of Example 1,4-(benzo[1,3]dioxol-5-yl)methylpiperazine (626 mg, 2.85 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.66 mmol) and N-methylmorpholine (0.42 mL, 3.82 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.48-2.49 (m, 4H), 3.41 (br, 6H), 5.98 (s,2H), 6.82-6.86 (m, 2H), 7.22 (d, J=7.4 Hz, 1H), 7.36-7.41 (m, 4H), 7.54(d, J=6.8 Hz, 1H), 7.56 (d, J=16.8 Hz, 1H), 7.62 (d, J=16.8 Hz, 1H),7.76 (d, J=8.4 Hz, 2H), 8.19 (d, J=7.4 Hz, 1H), 13.2 (br, 1H). APCI-MS(m/z); 467 [M+H]⁺

EXAMPLE 32(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-ethoxycarbonylpiperazine(Compound 32)

In a similar manner to Example 5, Compound 32 (346 mg, 45%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in Step 6 of Example 1, 1-piperazine carboxylic acid ethylester (0.42 mL, 2.84 mmol), 1-hydroxybenzotriazole monohydrate (332 mg,2.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(510 mg, 2.67 mmol) and N-methylmorpholine (0.42 mL, 3.82 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.18 (t, J=7.1 Hz, 3H), 3.27-3.43 (m, 8H),4.05 (q, J=7.1 Hz, 2H), 7.21 (t, J=7.1 Hz, 1H), 7.37-7.45 (m, 3H),7.53-7.67 (m, 3H), 7.78 (d, J=8.2 Hz, 2H), 8.19 (brd, J=8.2 Hz, 1H),13.2 (br, 1H). ESI-MS (m/z); 405 [M+H]⁺

EXAMPLE 33(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-methoxypiperidinehydrochloride (Compound 33)

In a similar manner to Example 5, a free base of Compound 33 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.30 g,1.14 mmol) obtained in Step 6 of Example 1, 4-methoxypiperidine (200 mg,1.71 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(305 mg, 1.60 mmol) and N-methylmorpholine (0.3 mL, 32.28 mmol), andthen the free base of Compound 33 was dissolved in ethyl acetate (5.00mL) and was added with 4 moL/L hydrogen chloride-dioxane solution (1.00mL) followed by stirring at room temperature for 30 minutes. Theprecipitate in the reaction mixture was filtered to obtain Compound 33(45.7 mg, 10%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.43 (br, 2H), 1.83-1.90 (m, 2H), 3.26 (s,3H), 3.40-3.47 (m, 1H), 4.64 (br, 4H), 7.20 (d, J=8.1 Hz, 1H), 7.36-7.41(m, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.52 (d, J=16.6 Hz, 1H), 7.57 (d, J=8.1Hz, 1H), 7.62 (d, J=16.6 Hz, 1H), 7.76 (d, J=8.1 Hz, 2H), 8.19 (d, J=8.1Hz, 1H). ESI-MS (m/z); 362 [M+H]⁺

EXAMPLE 34(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-methanesulfonylpiperidinehydrochloride (Compound 34)

In a similar manner to Example 5, a free base of Compound 34 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.40 g,1.52 mmol) obtained in Step 6 of Example 1, 4-methanesulfonylpiperidine(469 mg, 2.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (410 mg, 2.13 mmol) and N-methylmorpholine (0.34 mL, 3.03mmol), and then the free base of Compound 34 was dissolved in ethylacetate (5.00 mL) and was added with 4 moL/L hydrogen chloride-ethylacetate solution (1.00 mL), followed by stirring at room temperature for30 minutes. The precipitate in the reaction mixture was filtered toobtain Compound 34 (8.2 mg, 1.2%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.16 (br, 2H), 3.37 (br, 6H), 3.82 (s, 3H),3.91 (br, 1H), 7.22 (d, J=8.2 Hz, 1H), 7.31-7.43 (m, 1H), 7.33 (d, J=8.2Hz, 2H), 7.57 (d, J=16.6 Hz, 1H), 7.71 (d, J=16.6 Hz, 1H), 7.83 (d,J=8.2 Hz, 1H), 7.96 (d, J=8.2 Hz, 2H), 8.21 (d, J=8.2 Hz, 1H). ESI-MS(m/z); 410 [M+H]⁺

EXAMPLE 35(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(2-pyridyl)piperazinehydrochloride (Compound 35)

In a similar manner to Example 5, a free base of Compound 35 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.50 g,1.89 mmol) obtained in Step 6 of Example 1, 2-pyridylpiperazine (671 mg,2.84 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(510 mg, 2.67 mmol) and N-methylmorpholine (0.84 mL, 7.64 mmol), andthen the free base of Compound 35 was dissolved in acetic acid (5.00 mL)and was added with 4 moL/L hydrogen chloride-ethyl acetate solution(1.00 mL), followed by stirring at room temperature for 30 minutes. Theprecipitate in the reaction mixture was filtered to obtain Compound 35(190 mg, 23%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.60-3.81 (m, 8H), 6.96 (brt, J=7.1, 0.9 Hz,1H), 7.21 (t, J=7.2 Hz, 1H), 7.29-7.40 (m, 2H), 7.47-7.62 (m, 4H), 7.65(d, J=16.4 Hz, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.95-8.06 (m, 2H), 8.19(brd, J=8.1 Hz, 1H). APCI-MS (m/z); 410 [M+H]⁺

EXAMPLE 36(E)-4-acetyl-1-{3-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinehydrochloride (Compound 36)

In a similar manner to Example 5, a free base of Compound 36 wasobtained using (E)-3-(2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg,1.89 mmol) obtained in a similar manner to Step 6 of Example 1,N-acetylpiperazine (490 mg, 3.82 mmol), 1-hydroxybenzotriazolemonohydrate (332 mg, 2.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.66 mmol) and N-methylmorpholine (0.42 mL, 3.82 mmol), and then thefree base of Compound 36 was dissolved in ethyl acetate (5.00 mL) andwas added with 4 moL/L hydrogen chloride-ethyl acetate solution (1.00mL), followed by stirring at room temperature for 30 minutes. Theprecipitate in the reaction mixture was filtered to obtain Compound 36(491 mg, 69%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.02 (s, 3H), 3.51-3.61 (brm, 8H), 7.19 (t,1H, J=7.9 Hz), 7.30 (brd, J=7.7 Hz, 1H), 7.39 (brd, J=5.8 Hz, 1H),7.44-7.66 (m, 4H), 7.75 (brm, 1H), 7.80 (brd, J=7.6 Hz, 1H), 8.21 (d,J=8.2 Hz, 1H). APCI-MS (m/z); 375 [M+H]⁺

EXAMPLE 37 (E)-4-{3-[2-(1H-indazol-3-yl)vinyl]benzoyl}morpholinehydrochloride (Compound 37)

In a similar manner to Example 5, a free base of Compound 37 wasobtained using (E)-3-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg,1.89 mmol) obtained in a similar manner to Step 6 of Example 1,morpholine (0.33 mL, 3.82 mmol), 1-hydroxybenzotriazole monohydrate (332mg, 2.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (510 mg, 2.66 mmol) and N-methylmorpholine (0.42 mL, 3.82mmol), and then the free base of Compound 37 was dissolved in ethylacetate (5.00 mL) and was added with 4 moL/L hydrogen chloride-ethylacetate solution (1.00 mL), followed by stirring at room temperature for30 minutes. The precipitate in the reaction mixture was filtered toobtain Compound 37 (240 mg, 34%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.50-3.90 (brm, 8H), 7.20 (brt, J=7.8 Hz,1H), 7.27 (brd, J=7.6 Hz, 1H), 7.39 (brd, J=7.8 Hz, 1H), 7.43-7.66 (m,4H), 7.73 (m, 1H), 7.80 (brd, J=7.9 Hz, 1H), 8.21 (d, J=8.2 Hz, 1H).APCI-MS (m/z); 334 [M+H]⁺

EXAMPLE 38(E)-N-[2-(acetylamino)ethyl]-3-[2-(1H-indazol-3-yl)vinyl]benzamidehydrochloride (Compound 38)

In a similar manner to Example 5, Compound 38 (240 mg, 36%) was obtainedusing (E)-3-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in a similar manner to Step 6 of Example 1,N-acetylethylenediamine (290 mg, 3.82 mmol), 1-hydroxybenzotriazolemonohydrate (332 mg, 2.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.66 mmol) and N-methylmorpholine (420 μL, 3.82 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.82 (s, 3H), 3.22-3.35 (m, 4H), 7.21 (dt,J=7.9, 0.7 Hz, 1H), 7.37-7.99 (m, 7H), 8.19 (brs, 1H), 8.20 (brt, J=8.4Hz, 1H), 13.3 (brs, 1H). ESI-MS (m/z); 349 [M+H]⁺

EXAMPLE 39(E)-N-(1-acetylpiperidin-4-yl)-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 39)

In a similar manner to Example 5, Compound 39 (156 mg, 21%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in Step 6 of Example 1, 4-amino-1-acetylpiperidine (507 mg,2.84 mmol), 1-hydroxybenzotriazole monohydrate (332 mg, 2.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.67 mmol) and N-methylmorpholine (650 μL, 5.73 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.53-1.62 (m, 2H), 1.72-1.78 (m, 2H),1.98-2.07 (m, 2H), 2.82 (brd, J=10.7 Hz, 2H), 3.32 (s, 3H), 3.79 (m,1H), 7.18-7.42 (m, 3H), 7.50-7.57 (m, 2H), 7.66 (d, J=16.2 Hz, 1H), 7.78(d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 8.19 (brd, J=8.1 Hz, 1H),13.2 (br, 1H). ESI-MS (m/z); 389 [M+H]⁺

EXAMPLE 40(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(pivaloyl)piperazine(Compound 40)

In a similar manner to Example 5, Compound 40 (74.7 mg, 10%) wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg,1.89 mmol) obtained in Step 6 of Example 1, N-pivaloylpiperazine (587mg, 2.84 mmol), 1-hydroxybenzotriazole monohydrate (332 mg, 2.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.67 mmol) and N-methylmorpholine (1.04 mL, 9.55 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.19 (s, 9H), 3.31-3.59 (m, 8H), 7.21 (t,J=7.9 Hz, 1H), 7.38 (d, J=8.2 Hz, 2H), 7.49 (t, J=8.4 Hz, 1H), 7.50-7.67(m, 3H), 7.78 (d, J=8.2 Hz, 2H), 8.19 (brd, J=8.3 Hz, 1H), 13.2 (br,1H). ESI-MS (m/z); 417 [M+H]⁺

EXAMPLE 41(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(morpholinocarbonyl)piperazine(Compound 41)

In a similar manner to Example 5, Compound 41 (491 mg, 58%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in Step 6 of Example 1, N-morpholinocarbonylpiperazinehydrochloride (223 mg, 0.947 mmol), 1-hydroxybenzotriazole monohydrate(333 mg, 2.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (510 mg, 2.67 mmol) and N-methylmorpholine (1.00 mL, 9.55mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.15-3.28 (m, 8H), 3.54-3.57 (m, 8H), 7.21(t, J=7.9 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.43 (t, J=7.8 Hz, 1H),7.49-7.69 (m, 3H), 7.71 (d, J=8.4 Hz, 2H), 8.19 (brd, J=8.2 Hz, 1H),13.2 (br, 1H). ESI-MS (m/z); 446 [M+H]⁺

EXAMPLE 42(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(tert-butoxycarbonylamino)piperidine(Compound 42)

In a similar manner to Example 5, Compound 42 (242 mg, 29%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in Step 6 of Example 1, 4-(tert-butoxycarbonylamino)piperidine(538 mg, 2.84 mmol), 1-hydroxybenzotriazole monohydrate (332 mg, 2.46mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510mg, 2.67 mmol) and N-methylmorpholine (0.420 mL, 3.82 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.14-1.16 (m, 2H), 1.37 (s, 9H), 1.61-1.98(m, 2H), 2.88-3.31 (m, 2H), 3.51 (br, 2H), 4.29 (br, 1H), 6.88 (d, J=7.1Hz, 1H), 7.21 (t, J=7.1 Hz, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.41 (t, J=7.9Hz, 1H), 7.66-7.70 (m, 3H), 7.77 (d, J=8.3 Hz, 2H), 8.19 (brd, J=8.1 Hz,1H), 13.2 (br, 1H). ESI-MS (m/z); 447 [M+H]⁺

EXAMPLE 43(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(acetylamino)piperidine(Compound 43)

In a similar manner to Example 5, Compound 43 (283 mg, 39%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in Step 6 of Example 1, 4-(acetylamino)piperidine (404 mg, 2.84mmol), 1-hydroxybenzotriazole monohydrate (332 mg, 2.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.67 mmol) and N-methylmorpholine (0.42 mL, 3.82 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.32 (brm, 2H), 1.78-1.98 (m, 2H), 1.79 (s,3H), 3.06 (brm, 2H), 3.79-3.82 (m, 2H), 4.15 (m, 1H), 7.18-7.25 (m, 1H),7.37-7.41 (m, 3H), 7.48-7.66 (m, 3H), 7.76-7.86 (m, 3H), 8.19 (brd,J=8.1 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 389 [M+H]⁺

EXAMPLE 44(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(isonicotinoyl)piperazine(Compound 44)

In a similar manner to Example 5, Compound 44 (108 mg, 13%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (477 mg, 1.81 mmol)obtained in Step 6 of Example 1, 4-(isonicotinoyl)piperazinedihydrochloride (617 mg, 2.71 mmol), 1-hydroxybenzotriazole monohydrate(332 mg, 2.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (510 mg, 2.67 mmol) and N-methylmorpholine (1.00 mL, 9.55mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.36-3.70 (m, 8H), 7.22 (t, 1H, J=7.4 Hz),7.38-7.67 (m, 8H), 7.80 (d, 2H, J=8.1 Hz), 8.20 (d, 1H, J=8.2 Hz), 8.68(d, 2H, J=5.8 Hz), 13.2 (br, 1H). ESI-MS (m/z); 438 [M+H]⁺

EXAMPLE 45(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(nicotinoyl)piperazine(Compound 45)

In a similar manner to Example 5, Compound 45 (58.6 mg, 7%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in Step 6 of Example 1, 4-(nicotinoyl)piperazine hydrochloride(617 mg, 2.71 mmol), 1-hydroxybenzotriazole monohydrate (332 mg, 2.46mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510mg, 2.67 mmol) and N-methylmorpholine (1.00 mL, 9.55 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.33-3.58 (m, 8H), 7.22 (t, J=7.9 Hz, 1H),7.37-7.68 (m, 7H), 7.83 (dd, J=8.1, 0.9 Hz, 3H), 8.20 (d, J=8.1 Hz, 1H),8.68 (dd, J=4.9, 1.5 Hz, 2H), 13.2 (br, 1H). ESI-MS (m/z); 438 [M+H]⁺

EXAMPLE 46(E)-1-{4-[2-(1H-indazol-3-yl)-vinyl]benzoyl}-4-benzoylpiperazine(Compound 46)

In a similar manner to Example 5, Compound 46 (168 mg, 20%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in Step 6 of Example 1, 4-benzoylpiperazine hydrochloride (643mg, 2.71 mmol), 1-hydroxybenzotriazole monohydrate (332 mg, 2.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.67 mmol) and N-methylmorpholine (1.00 mL, 9.55 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.36-3.70 (m, 8H), 7.22 (t, J=7.1 Hz, 1H),7.38-7.68 (m, 11H), 7.79 (d, J=8.1 Hz, 2H), 8.20 (d, J=8.2 Hz, 1H), 13.2(br, 1H). ESI-MS (m/z); 437 [M+H]⁺

EXAMPLE 47(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(methanesulfonyl)piperazine(Compound 47)

In a similar manner to Example 5, Compound 47 (100 mg, 13%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in Step 6 of Example 1, 4-(methanesulfonyl)piperazinehydrochloride (570 mg, 2.71 mmol), 1-hydroxybenzotriazole monohydrate(332 mg, 2.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (510 mg, 2.67 mmol) and N-methylmorpholine (0.65 mL, 5.91mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.92 (s, 3H), 3.15-3.25 (m, 6H), 3.51-3.65(m, 2H), 7.22 (t, J=7.9 Hz, 1H), 7.40 (t, J=8.3 Hz, 1H), 7.46 (d, J=7.9Hz, 2H), 7.52-7.69 (m, 3H), 7.81 (d, J=7.9 Hz, 2H), 8.21 (d, J=7.8 Hz,1H), 13.2 (br, 1H). ESI-MS (m/z); 411 [M+H]⁺

EXAMPLE 48(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-[(1H-imidazol-1-yl)carbonyl]piperazine(Compound 48)

A solution of dihydrochloride of Compound 18 (400 mg, 1.09 mmol) in THF(20 mL) was added with ethylamine (177 mg, 2.18 mmol) and (352 mg, 2.18mmol), followed by stirring at room temperature for 1.5 hours. Thereaction mixture was added with water and was extracted with ethylacetate. The organic layer was washed with saturated brine, and wasdried over anhydrous magnesium sulfate. The solvent was evaporated andthe residue was purified by preparative thin-layer chromatography(chloroform/acetone=1/1) to obtain Compound 48 (350 mg, 44%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.59 (br, 8H), 7.04 (d, J=2.1 Hz, 1H), 7.21(d, J=8.2 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.48(d, J=2.1 Hz, 1H), 7.54 (d, J=16.6 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.64(d, J=16.6 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 8.05 (d, J=8.2 Hz, 1H), 8.20(d, J=8.2 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 427 [M+H]⁺

EXAMPLE 49(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(ethoxycarbonyl)piperidine(Compound 49)

In a similar manner to Example 5, Compound 49 (3.04 g, 59%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (3.38 g, 12.8 mmol)obtained in Step 6 of Example 1, ethyl isonipecotate (2.4 mL, 15.4mmol), 1-hydroxybenzotriazole monohydrate (2.94 g, 19.2 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.68 g,19.2 mmol) and N-methylmorpholine (2.8 mL, 25.6 mmol).

¹H-NMR (300 MHz, DMSO-d₆) δ 1.02 (dd, J=1.83, 6.1 Hz, 2H), 1.18 (t,J=7.2 Hz, 3H), 1.47-1.58 (m, 2H), 1.85 (brs, 2H), 2.59-2.67 (m, 1H),3.03 (brs, 2H), 4.07 (t, J=7.2 Hz, 2H), 7.18-7.27 (m, 1H), 7.36-7.41 (m,3H), 7.48-7.59 (m, 2H), 7.63-7.66 (m, 1H), 7.77 (d, J=8.3 Hz, 2H), 8.20(d, J=8.3 Hz, 1H), 13.2 (s, 1H). ESI-MS (m/z); 404 [M+H]⁺

EXAMPLE 50(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-carboxypiperidine(Compound 50)

Compound 49 (1.0 g, 2.80 mmol) was dissolved in ethanol (40 mL), thenthe solution was added with 2 mol/L aqueous sodium hydroxide solution(15.0 mL) at 0° C., and was warmed to room temperature. After stirringfor 6 hours, the reaction mixture was neutralized with 2 mol/Lhydrochloric acid and was extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and was concentrated. Theresidue was recrystallized from ethyl acetate and methanol to obtainCompound 50 (654 mg, 70%).

¹H-NMR (300 MHz, DMSO-d₆) δ 1.44-1.53 (m, 2H), 1.85 (brm, 2H), 2.71(brs, 2H), 3.04-3.34 (brm, 3H), 4.30 (brm, 1H), 7.20 (m, 1H), 7.40 (dd,J=3.3, 1.4 Hz, 2H), 7.50-7.65 (m, 4H), 7.77 (d, J=8.3 Hz, 2H), 8.19 (d,J=8.1 Hz, 1H), 13.2 (s, 1H). ESI-MS (m/z); 376 [M+H]⁺

EXAMPLE 51(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(morpholinocarbonyl)piperidine(Compound 51)

In a similar manner to Example 5, Compound 51 (101 mg, 34%) was obtainedusing Compound 50 (250 mg, 0.67 mmol), morpholine (0.087 mL, 0.99 mmol),1-hydroxybenzotriazole monohydrate (133 mg, 0.870 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (178 mg,0.93 mmol).

¹H-NMR (300 MHz, DMSO-d₆) δ 1.45-1.65 (m, 4H), 2.93-3.32 (brm, 3H),3.43-4.03 (brm, 10H), 7.18-7.23 (m, 1H), 7.37-7.41 (m, 2H), 7.50-7.65(m, 4H), 7.76 (d, J=8.1 Hz, 2H), 8.20 (d, J=8.1 Hz, 1H), 13.20 (s, 1H),7.79 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.1 Hz, 1H). ESI-MS (m/z); 445 [M+H]⁺

EXAMPLE 52 methyl {(E)-4-[2-(1H-indazol-3-yl)vinyl]benzoylamino}acetate(Compound 52)

In a similar manner to Example 5, Compound 52 (1.65 g, 87%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (1.50 g, 5.68 mmol)obtained in Step 6 of Example 1, glycine methyl ester hydrochloride (856mg, 6.82 mmol), 1-hydroxybenzotriazole monohydrate (1.30 g, 8.52 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.63 g,8.52 mmol) and N-methylmorpholine (1.87 mL, 17.0 mmol).

¹H-NMR (300 MHz, DMSO-d₆) δ 3.62 (s, 3H), 3.90 (dd, J=17.8, 5.7 Hz, 2H),7.21 (m, 1H), 7.40 (m, 1H), 7.54 (m, 1H), 7.67 (m, 1H), 7.81 (d, J=8.3Hz, 2H), 7.90 (d, J=8.3 Hz, 2H), 8.20 (d, J=7.9 Hz, 1H), 8.35 (m, 1H),8.79 (m, 1H), 13.2 (s, 1H). ESI-MS (m/z); 336 [M+H]⁺

EXAMPLE 53 {(E)-4-[2-(1H-indazol-3-yl)vinyl]benzoylamino}acetic acid(Compound 53)

Compound 52 (1.65 g, 4.93 mmol) was dissolved in THF (30 mL), then thesolution was added with 2 mol/L aqueous sodium hydroxide solution (15.0mL) at 0° C., followed by stirring at 70° C. for 1 hour. The reactionmixture was neutralized with 2 mol/L hydrochloric acid, then wasextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, and was concentrated. The residue was recrystallizedfrom ethyl acetate and methanol to obtain Compound 53 (662 mg, 42%).

¹H-NMR (300 MHz, DMSO-d₆) δ 3.90 (d, J=5.8 Hz, 2H), 7.21 (m, 1H), 7.39(m, 1H), 7.51-7.71 (m, 3H), 7.83 (dd, J=21.8, 8.4 Hz, 4H), 8.21 (d,J=8.2 Hz, 1H), 8.76 (m, 1H), 13.2 (brs, 1H). ESI-MS (m/z); 322 [M+H]⁺

EXAMPLE 54(E)-4-acetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]-2-methoxybenzoyl}piperazine(Compound 54)

In a similar manner to Example 5, Compound 54 (108 mg, 14%) was obtainedusing (E)-4-[2-(1H-indazol73-yl)vinyl]-2-methoxybenzoic acid (500 mg,1.70 mmol), N-acetylpiperazine (327 mg, 2.55 mmol),1-hydroxybenzotriazole monohydrate (300 mg, 2.22 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (456 mg,2.40 mmol) and N-methylmorpholine (0.40 mL, 3.41 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.99 (s, 3H), 3.13-3.66 (brm, 8H), 3.90 (s,3H), 7.22 (t, J=8.1 Hz, 2H), 7.34-7.43 (m, 2H), 7.48 (d, J=16.5 Hz, 1H),7.51-7.57 (m, 2H), 7.66 (d, J=16.5 Hz, 1H), 8.21 (d, J=8.2 Hz, 1H), 13.2(brs, 1H). ESI-MS (m/z); 405 [M+H]⁺

EXAMPLE 55(E)-4-cyclopropanecarbonyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 55)

In a similar manner to Example 5, Compound 55 (343 mg, 87%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 1.09 mmol),cyclopropylcarboxylic acid (0.078 mL, 0.987 mmol),1-hydroxybenzotriazole monohydrate (173 mg, 1.28 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg,1.38 mmol) and N-methylmorpholine (0.20 mL, 1.82 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.00 (d, J=6.6 Hz, 4H), 2.81 (m, 1H),3.54-3.98 (m, 8H), 7.21 (dt, J=7.9, 1.1 Hz, 1H), 7.36-7.67 (m, 6H), 7.79(d, J=8.2 Hz, 2H), 8.20 (d, J=8.2 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z);401 [M+H]⁺

EXAMPLE 56(E)-4-isobutyryl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 56)

In a similar manner to Example 5, Compound 56 (201 mg, 51%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 1.09 mmol),2-methylpropionic acid (0.092 mL, 0.987 mmol), 1-hydroxybenzotriazolemonohydrate (173 mg, 1.28 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg,1.38 mmol) and N-methylmorpholine (0.40 mL, 3.64 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 0.68-0.78 (m, 6H), 3.33-3.79 (m, 9H), 7.21(dt, J=8.1, 1.5 Hz, 1H), 7.39 (dt, J=8.4, 1.5 Hz, 1H), 7.45 (d, J=8.3Hz, 2H), 7.51-7.67 (m, 3H), 7.79 (d, J=8.2 Hz, 2H), 8.20 (d, J=8.2 Hz,1H), 13.2 (br, 1H). ESI-MS (m/z); 403 [M+H]⁺

EXAMPLE 57(E)-4-(2-thiophencarbonyl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 57)

In a similar manner to Example 5, Compound 57 (382 mg, 88%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 1.09 mmol),2-thiophenecarboxylic acid (127 mg, 0.987 mmol), 1-hydroxybenzotriazolemonohydrate (173 mg, 1.28 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg,1.38 mmol) and N-methylmorpholine (0.400 mL, 3.64 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.38-3.98 (m, 8H), 7.13 (dt, J=8.6, 2.3 Hz,1H), 7.21 (t, J=7.4 Hz, 1H), 7.37-7.68 (m, 7H), 7.78 (t, J=8.3 Hz, 3H),8.20 (d, J=8.3 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 443 [M+H]⁺

EXAMPLE 58(E)-4-(3-thiophenecarbonyl)-1-{4-[2-(1H-indazol-3-yl)vinyl-]benzoyl}piperazine(Compound 58)

In a similar manner to Example 5, Compound 58 (356 mg, 82%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 1.09 mmol),3-thiophenecarboxylic acid (127 mg, 0.987 mmol), 1-hydroxybenzotriazolemonohydrate (173 mg, 1.28 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg,1.38 mmol) and N-methylmorpholine (0.40 mL, 3.64 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.38-3.98 (m, 8H), 7.13 (dt, J=8.6, 2.3 Hz,1H), 7.21 (t, J=7.4 Hz, 1H), 7.37-7.68 (m, 7H), 7.67-7.88 (m, 3H), 8.20(d, J=8.2 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 443 [M+H]⁺

EXAMPLE 59(E)-4-ethylaminocarbonyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 59)

A solution of dihydrochloride of Compound 18 (400 mg, 1.09 mmol) in THF(20 mL) was added with triethylamine (0.42 mL, 3.01 mmol) andethylisodyanate (117 mg, 1.65 mmol), followed by stirring at roomtemperature for 3 hours. The reaction mixture was added with water, anddeposited crystal was collected by filtration and was dried to obtainCompound 59 (218 mg, 55%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.00 (t, J=7.1 Hz, 3H), 3.00-3.07 (m, 2H),3.33-3.44 (m, 8H), 6.55 (t, J=5.3 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.38(d, J=8.4 Hz, 1H), 7.43 (t, J=8.3 Hz, 2H), 7.50-7.67 (m, 3H), 7.78 (d,J=8.3 Hz, 2H), 8.20 (d, J=8.1 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 404[M+H]⁺

EXAMPLE 60(E)-4-butyryl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 60)

In a similar manner to Example 5, Compound 60 (221 mg, 61%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 1.09 mmol), n-butanoicacid (0.082 mL, 0.896 mmol), 1-hydroxybenzotriazole monohydrate (173 mg,1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(265 mg, 1.38 mmol) and N-methylmorpholine (0.40 mL, 3.64 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 0.88 (t, J=7.4 Hz, 3H), 1.50 (q, J=7.4 Hz,2H), 2.28 (t, J=7.3 Hz, 2H), 3.81-3.98 (m, 8H), 7.21 (t, J=7.4 Hz, 1H),7.38 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.53-7.67 (m, 3H), 7.78(d, J=8.2 Hz, 2H), 8.20 (d, J=8.2 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z);403 [M+H]⁺

EXAMPLE 61(E)-4-aminoacetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinehydrochloride (Compound 61)

In a similar manner to Example 5,(E)-4-(tert-butoxycarbonylamino)acetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinewas obtained using dihydrochloride of Compound 18 (800 mg, 2.18 mmol),N-(tert-butoxycarbonyl)glycine (314 mg, 1.79 mmol),1-hydroxybenzotriazole monohydrate (315 mg, 2.56 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (482 mg,2.51 mmol) and N-methylmorpholine (0.80 mL, 7.28 mmol). In a similarmanner to Example 18,(E)-4-(tert-butoxycarbonylamino)acetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinewas treated with 10% hydrogen chloride-methanol solution to obtainCompound 61 (448 mg, 64%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.41-3.68 (m, 8H), 3.88-3.92 (brd, J=2.9 Hz,2H), 7.21 (t, J=7.9 Hz, 1H), 7.37-7.67 (m, 7H), 7.80 (d, J=8.3 Hz, 2H),8.14 (brm, 1H), 8.20 (d, J=8.3 Hz, 1H). ESI-MS (m/z); 390 [M+H]⁺

EXAMPLE 62(E)-N-(2-oxo-2-morpholinoethyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 62)

In a similar manner to Example 5, Compound 62 (105 mg, 36%) was obtainedusing Compound 53 (250 mg, 0.776 mmol), morpholine (0.098 mL, 1.12mmol), 1-hydroxybenzotriazole monohydrate (149 mg, 0.97 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (200 mg,1.04 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.15-3.31 (m, 1H), 3.40-3.59 (m, 8H), 4.13(d, J=5.7 Hz, 2H), 7.21 (t, J=7.7 Hz, 1H), 7.35-7.42 (m, 2H), 7.52-7.65(m, 2H), 7.72 (d, J=15.2 Hz, 1H), 7.86 (dd, J=24.8, 8.4 Hz, 4H), 8.21(d, J=8.3 Hz, 1H), 8.59 (t, J=5.9 Hz, 1H). ESI-MS (m/z); 391 [M+H]⁺

EXAMPLE 63(E)-N-[2-(diethylamino)ethyl]-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 63)

In a similar manner to Example 5, Compound 63 (3.00 g, 55%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (4.00 g, 15.1 mmol),N,N-diethylethylenediamine (2.60 mL, 18.2 mmol), 1-hydroxybenzotriazolemonohydrate (3.00 g, 19.70 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.10 g,21.2 mmol) and N-methylmorpholine (3.40 mL, 30.3 mmol).

¹H-NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.5 Hz, 6H), 2.54 (m, 8H), 7.20(m, 1H), 7.40 (m, 1H), 7.51-7.69 (m, 3H), 7.81 (dd, J=18.3, 8.3 Hz, 4H),8.20 (d, J=8.1 Hz, 1H), 8.40 (m, 1H), 13.2 (s, 1H). ESI-MS (m/z); 363[M+H]⁺

EXAMPLE 64 (E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-aminopiperidine(Compound 64)

The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid(500 mg, 1.89 mmol) obtained in Step 6 of Example 1,4-(tert-butoxycarbonylamino)piperidine (538 mg, 2.84 mmol),1-hydroxybenzotriazole monohydrate (332 mg, 2.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.67 mmol) and N-methylmorpholine (0.420 mL, 3.82 mmol) in a similarmanner to Example 5, was dissolved in methanol (10.0 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution (5.0mL), followed by heating under reflux at 60° C. for 90 minutes. Thereaction mixture was concentrated under reduced pressure, the residuewas extracted after adding with a saturated aqueous potassium carbonatesolution and ethyl acetate. The crude product was crystallized fromethyl acetate to obtain Compound 64 (435 mg, 66%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.15-1.20 (m, 2H), 1.72-2.00 (m, 2H),2.79-3.60 (m, 7H), 7.22 (dd, J=7.9, 7.9 Hz, 1H), 7.38 (d, J=8.3 Hz, 2H),7.37-7.43 (m, 1H), 7.54 (d, J=16.9 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.63(d, J=16.9 Hz, 1H), 7.78 (d, J=8.3 Hz, 2H), 8.21 (d, J=8.3 Hz, 1H).ESI-MS (m/z); 347 [M+H]⁺

EXAMPLE 65(E)-4-methoxyacetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 65)

In a similar manner to Example 5, Compound 65 (225 mg, 62%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 1.09 mmol), methoxyaceticacid (0.069 mL, 0.896 mmol), 1-hydroxybenzotriazole monohydrate (173 mg,1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(265 mg, 1.38 mmol) and N-methylmorpholine (0.40 mL, 3.64 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.28 (s, 3H), 3.33-3.49 (m, 8H), 4.10 (s,2H), 7.21 (t, J=7.3 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.44 (d, J=8.3 Hz,2H), 7.51-7.67 (m, 3H), 7.79 (d, J=8.3 Hz, 2H), 8.20 (d, J=8.1 Hz, 1H),13.2 (br, 1H). ESI-MS (m/z); 405 [M+H]⁺

EXAMPLE 66(E)-4-(3-methylbutyryl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 66)

In a similar manner to Example 5, Compound 66 (207 mg, 56%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 1.09 mmol), isovalericacid (0.094 mL, 0.896 mmol), 1-hydroxybenzotriazole monohydrate (176 mg,1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(265 mg, 1.38 mmol) and N-methylmorpholine (0.400 mL, 3.64 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 0.89 (d, J=6.6 Hz, 6H), 1.93-2.03 (m, 1H),2.21 (d, J=6.8 Hz, 2H), 3.39-3.52 (m, 8H), 7.21 (t, J=7.3 Hz, 1H), 7.38(d, J=8.8 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.51-7.67 (m, 3H), 7.79 (d,J=8.3 Hz, 2H), 8.20 (d, J=8.1 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 417[M+H]⁺

EXAMPLE 67(E)-4-(4-methylphenylsulfonyl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 67)

In a similar manner to Example 47, Compound 67 (210 mg, 48%) wasobtained using dihydrochloride of Compound 18 (400 mg, 1.09 mmol),triethylamine (0.420 mL, 3.01 mmol) and p-toluenesulfonyl chloride (376mg, 1.97 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.42 (s, 3H), 2.94-3.26 (m, 4H), 3.39-3.57(m, 4H), 7.20 (t, J=7.9 Hz, 1H), 7.35-7.64 (m, 10H), 7.74 (d, J=8.3 Hz,2H), 8.18 (d, J=8.3 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 487 [M+H]⁺

EXAMPLE 68(E)-4-(2-methyl-2-hydroxypropionyl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 68)

In a similar manner to Example 5, Compound 68 (223 mg, 60%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 1.09 mmol),α-hydroxyisobutyric acid (93.2 mg, 0.896 mmol), 1-hydroxybenzotriazolemonohydrate (176 mg, 1.28 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg,1.38 mmol) and N-methylmorpholine (0.40 mL, 3.64 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.52 (s, 6H), 3.71-3.99 (m, 8H), 5.65 (br,1H), 7.41 (t, J=7.3 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.65 (d, J=8.4 Hz,2H), 7.71-7.87 (m, 3H), 7.98 (d, J=8.2 Hz, 2H), 8.40 (d, J=8.1 Hz, 1H),13.4 (br, 1H). ESI-MS (m/z); 419 [M+H]⁺

EXAMPLE 69(E)-4-acetyl-1-{2-chloro-4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 69)

In a similar manner to Example 5, Compound 69 (42 mg, 30%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]-2-chlorobenzoic acid (100 mg,0.34 mmol), N-acetylpiperazine (64 mg, 0.50 mmol),1-hydroxybenzotriazole monohydrate (67 mg, 0.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (90 mg, 0.47mmol) and N-methylmorpholine (0.40 mL, 3.41 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.04 (s, 3H), 3.12-3.91 (br, 8H), 6.71-7.69(m, 8H), 7.99 (d, J=8.1 Hz, 1H). ESI-MS (m/z); 409 [M+H]⁺

EXAMPLE 70(E)-4-[2-(1H-indazol-3-yl)vinyl]-N-(methylcarbamoylmethyl)benzamide(Compound 70)

In a similar manner to Example 5, Compound 70 (63 mg, 24%) was obtainedusing Compound 53 (300 mg, 0.932 mmol), methylamine hydrochloride (65.0mg, 0.960 mmol), 1-hydroxybenzotriazole monohydrate (159 mg, 1.04 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (215 mg,1.12 mmol) and N-methylmorpholine (0.220 mL, 2.00 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.59 (d, J=4.6 Hz, 3H), 3.19-3.45 (m, 1H),3.82 (d, J=5.9 Hz, 2H), 7.20 (m, 1H), 7.39 (m, 1H), 7.51-7.71 (m, 3H),7.84 (dd, J=27.8, 8.4 Hz, 4H), 8.20 (d, J=8.1 Hz, 1H), 8.73 (m, 1H),13.2 (s, 1H). ESI-MS (m/z); 335 [M+H]⁺

EXAMPLE 71(E)-4-(N-acetylamino)acetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 71)

In a similar manner to Example 5, Compound 71 (320 mg, 83%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 1.09 mmol),N-acetylglycine (105 mg, 0.896 mmol), 1-hydroxybenzotriazole monohydrate(175 mg, 1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (265 mg, 1.38 mmol) and N-methylmorpholine (0.400 mL, 3.64mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.98 (s, 3H), 3.42-3.58 (m, 8H), 3.94-3.98(m, 2H), 7.21 (t, J=7.0 Hz, 1H), 7.40 (d, J=7.0 Hz, 1H), 7.45 (d, J=8.3Hz, 2H), 7.51-7.67 (m, 3H), 7.79 (d, J=8.3 Hz, 2H), 7.97 (t, J=5.5 Hz,1H), 8.20 (d, 7.9 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 432 [M+H)]⁺

EXAMPLE 72(E)-4-(3-hydroxy-2,2-dimethylpropionyl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 72)

In a similar manner to Example 5, Compound 72 (40 mg, 10%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 1.09 mmol),3-hydroxy-2,2-dimethylpropionic acid (106 mg, 0.896 mmol),1-hydroxybenzotriazole monohydrate (176 mg, 1.28 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg,1.38 mmol) and N-methylmorpholine (0.40 mL, 3.64 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.15 (s, 6H), 3.41-3.42 (m, 2H), 3.45-3.65(m, 8H), 4.58 (t, J=5.9 Hz, 1H), 7.21 (t, J=7.9 Hz, 1H), 7.38 (d, J=7.5Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.51-7.67 (m, 3H), 7.79 (d, J=8.3 Hz,2H), 8.20 (d, J=8.1 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 433 [M+H]⁺

EXAMPLE 73(E)-4-acetyl-1-{2-methyl-4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 73)

In a similar manner to Example 5, Compound 73 (37 mg, 16%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]-2-methylbenzoic acid (174 mg,0.60 mmol), N-acetylpiperazine (114 mg, 0.892 mmol),1-hydroxybenzotriazole monohydrate (118 mg, 0.873 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg,0.835 mmol) and N-methylmorpholine (0.40 mL, 3.41 mmol).

¹H-NMR (270 MHz, CDCl₃) δ 2.17 (s, 3H), 2.36 (s, 3H), 3.19-3.49 (br,4H), 3.57-3.85 (br, 4H), 6.86-7.52 (m, 8H), 8.04 (d, J=8.1 Hz, 1H).ESI-MS (m/z); 389 [M+H]⁺

EXAMPLE 74(E)-4-hydroxyacetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinehydrochloride (Compound 74)

In a similar manner to Example 5, a free base of Compound 74 wasobtained using dihydrochloride of Compound 18 (400 mg, 1.09 mmol),glycolic acid (68.0 mg, 0.896 mmol), 1-hydroxybenzotriazole monohydrate(178 mg, 1.29 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (265 mg, 1.38 mmol) and N-methylmorpholine (0.40 mL, 3.64mmol), and then the free base of Compound 74 was dissolved in1,4-dioxane (2.0 mL), and the solution was added with 4 moL/L hydrogenchloride-1,4-dioxane solution (2.0 mL), followed by stirring at roomtemperature for 30 minutes. The precipitate in the reaction mixture wasfiltered to obtain Compound 74 (200 mg, 52%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.41-3.52 (m, 4H), 3.55-3.65 (m, 4H), 4.10(s, 2H), 7.20 (t, J=7.0 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4Hz, 2H), 7.46-7.66 (m, 3H), 7.78 (d, J=8.4 Hz, 2H), 8.20 (d, J=8.4 Hz,1H). ESI-MS (m/z); 391 [M+H]⁺

EXAMPLE 75(E)-4-methoxycarbonyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinehydrochloride (Compound 75)

In a similar manner to Example 5, Compound 75 (1.00 g, 78%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (1.00 g, 2.97 mmol)obtained in Step 6 of Example 1, N-methoxycarbonylpiperazine (970 mg,4.47 mmol), 1-hydroxybenzotriazole monohydrate (520 mg, 3.85 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (800 mg,4.17 mmol) and N-methylmorpholine (1.30 mL, 11.8 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.41-3.52 (m, 4H), 3.61 (s, 3H), 3.78-4.00(m, 4H), 7.21 (t, J=7.8 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.44 (d, J=8.4Hz, 2H), 7.53 (d, J=16.1 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.63 (d,J=16.1 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 8.20 (d, J=8.3 Hz, 1H). ESI-MS(m/z); 391 [M+H]⁺

EXAMPLE 76 (E)-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}thiomorpholinehydrochloride (Compound 76)

In a similar manner to Example 5, a free base of Compound 76 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg,1.89 mmol) obtained in Step 6 of Example 1, thiomorpholine (0.307 mL,3.05 mmol), 1-hydroxybenzotriazole monohydrate (333 mg, 2.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.67 mmol) and N-methylmorpholine (1.00 mL, 9.55 mmol), and then thefree base of Compound 76 was dissolved in 1,4-dioxane (2.0 mL), and-thesolution was added with 4 moL/L hydrogen chloride-1,4-dioxane solution(2.0 mL), followed by stirring at room temperature for 30 minutes. Theprecipitate in the reaction mixture was filtered to obtain Compound 76(443 mg, 57%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.55-2.74 (m, 4H), 3.48-3.71 (m, 4H), 7.20(t, J=8.0 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.53(d, J=16.3 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.63 (d, J=16.3 Hz, 1H),7.77 (d, J=8.4 Hz, 2H), 8.19 (d, J=8.2 Hz, 1H). ESI-MS (m/z); 350 [M+H]⁺

EXAMPLE 77(E)-4-(1-methylcyclopropanecarbonyl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 77)

In a similar manner to Example 5, Compound 77 (311 mg, 67%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 1.09 mmol),1-methylcyclopropanecarboxylic acid (0.091 mL, 0.896 mmol),1-hydroxybenzotriazole monohydrate (176 mg, 1.28 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg,1.38 mmol) and N-methylmorpholine (0.40 mL, 3.64 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 0.48-0.57 (m, 2H), 0.80-0.84 (m, 2H), 1.24(s, 3H), 3.48-3.71 (m, 8H), 7.23 (t, J=7.1 Hz, 1H), 7.41 (t, J=8.2 Hz,1H), 7.47 (d, J=8.4 Hz, 2H), 7.53 (d, J=16.1 Hz, 1H), 7.58 (d, J=8.4 Hz,1H), 7.67 (d, J=16.3 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 8.22 (d, J=8.1 Hz,1H), 13.2 (br, 1H). ESI-MS (m/z); 415 [M+H]⁺

EXAMPLE 78 (E)-4-(3,3-dimethylbutyryl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine (Compound 78)

In a similar manner to Example 5, Compound 78 (201 mg, 52%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 1.09 mmol),tert-butylacetic acid (0.115 mL, 0.896 mmol), 1-hydroxybenzotriazolemonohydrate (176 mg, 1.28 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg,1.38 mmol) and N-methylmorpholine (0.400 mL, 3.64 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 0.98 (s, 9H), 2.25 (brs, 2H), 3.41-3.54 (m,8H), 7.21 (t, J=7.7 Hz, 1H), 7.38 (t, J=8.4 Hz, 1H), 7.44 (d, J=8.2 Hz,2H), 7.51 (d, J=16.2 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.67 (d, J=16.2Hz, 1H), 7.79 (d, J=8.2 Hz, 2H), 8.20 (d, J=8.2 Hz, 1H), 13.2 (br, 1H).ESI-MS (m/z); 431 [M+H]⁺

EXAMPLE 79(E)-N-[2-(ethoxycarbonyl)ethyl]-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 79)

In a similar manner to Example 5, Compound 79 (123 mg, 6%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (1.50 g, 5.68 mmol)obtained in Step 6 of Example 1, β-alanine ethyl ester hydrochloride(1.05 g, 6.81 mmol), 1-hydroxybenzotriazole monohydrate (1.30 g, 8.52mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.63g, 8.52 mmol) and N-methylmorpholine (1.87 mL, 17.0 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.17 (t, J=7.1 Hz, 3H), 2.58 (t, J=7.1 Hz,2H), 3.39-3.53 (m, 2H), 4.0 (q, J=7.1 Hz, 2H), 7.23-7.17 (m, 1H),7.36-7.42 (m, 1H), 7.49-7.72 (m, 3H), 7.79 (dd, J=16.3, 8.4 Hz, 4H),8.19 (d, J=8.1 Hz, 1H), 8.55 (m, 1H), 13.2 (s, 1H). ESI-MS (m/z); 364[M+H]⁺

EXAMPLE 80(E)-N-methyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperidine-4-carboxamide(Compound 80)

In a similar manner to Example 5, Compound 80 (22 mg, 7%) was obtainedusing Compound 50 (300 mg, 0.80 mmol), methylamine hydrochloride (64.8mg, 0.96 mmol), 1-hydroxybenzotriazole monohydrate (184 mg, 1.2 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg, 1.2mmol) and N-methylmorpholine (0.264 mL, 2.4 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.78 (d, J=4.4 Hz, 3H), 3.14-3.65 (m, 9H),7.18-7.24 (m, 1H), 7.36-7.42 (m, 1H), 7.50-7.68 (m, 3H), 7.78 (d, J=5.5Hz, 2H), 7.84 (d, J=8.4 Hz, 2H), 8.19 (d, J=8.1 Hz, 1H), 8.42 (d, J=4.5Hz, 1H), 13.2 (s, 1H). ESI-MS (m/z); 389 [M+H]⁺

EXAMPLE 81(E)-N,N-diethyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperidine-4-carboxamide(Compound 81)

In a similar manner to Example 5, Compound 81 (48 mg, 14%) was obtainedusing Compound 50 (300 mg, 0.80 mmol), diethylamine (0.099 mL, 0.96mmol), 1-hydroxybenzotriazole monohydrate (184 mg, 1.20 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg,1.20 mmol) and N-methylmorpholine (0.13 mL, 1.20 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 0.99 (t, J=7.1 Hz, 3H), 1.12 (t, J=7.1 Hz,3H), 1.51-1.59 (m, 4H), 2.49 (m, 1H), 2.82-3.29 (m, 4H), 3.35-3.43 (m,4H), 7.17-7.23 (m, 1H), 7.37-7.42 (m, 2H), 7.53-7.65 (m, 2H), 7.77 (d,J=8.2 Hz, 2H), 8.19 (d, J=8.1 Hz, 1H), 13.2 (s, 1H). ESI-MS (m/z); 431[M+H]⁺

EXAMPLE 82(E)-1-(tert-butoxycarbonyl)-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}homopiperazine(Compound 82)

In a similar manner to Example 5, Compound 82 (1.52 g, 30%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (3.00 g, 11.4 mmol)obtained in Step 6 of Example 1, 1-(tert-butoxycarbonyl)homopiperazine(3.41 g, 17.0 mmol), 1-hydroxybenzotriazole monohydrate (1.99 g, 14.7mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.05g, 15.9 mmol) and N-methylmorpholine (4.13 mL, 37.6 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.41 (s, 9H), 1.52 (m, 1H), 1.46 (m, 1H),3.33-3.69 (m, 8H), 7.21 (t, J=7.9 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.42(d, J=8.4 Hz, 2H), 7.53 (d, J=16.5 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.66(d, J=16.5 Hz, 1H), 7.77 (d, J=8.1 Hz, 2H), 8.20 (d, J=7.6 Hz, 1H), 13.2(br, 1H). ESI-MS (m/z); 447 [M+H]⁺

EXAMPLE 83(E)-4-{2-chloro-4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine-1-carboxylicacid 1,1-dimethylethylester (Compound 83)

In a similar manner to Example 5, Compound 83 (157 mg, 34%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]-2-chlorobenzoic acid (300 mg,1.00 mmol), N-(tert-butoxycarbonyl)piperazine (280 mg, 1.51 mmol),1-hydroxybenzotriazole monohydrate (199 mg, 1.30 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (268 mg,1.40 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.47 (s, 9H), 3.23-3.57 (m, 6H), 3.71-3.89(m, 2H), 7.26-7.32 (m, 3H), 7.42-7.55 (m, 4H), 7.62 (d, J=1.3 Hz, 1H),8.02 (d, J=8.1 Hz, 1H), 10.1-10.2 (brs, 1H). ESI-MS (m/z); 467 [M+H]⁺

EXAMPLE 84(E)-4-{2-methyl-4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine-1-carbaldehyde(Compound 84)

In a similar manner to Example 5, Compound 84 (4.5 mg, 13%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]-2-methylbenzoic acid (221 mg,0.761 mmol), N-formylpiperazine (0.120 mL, 1.13 mmol),1-hydroxybenzotriazole monohydrate (151 mg, 0.982 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (203 mg,1.06 mmol).

¹H-NMR (300 MHz, CDCl₃) δ 2.37 (s, 3H), 3.25-3.32 (br, 4H), 3.51-3.85(br, 4H), 6.88 (m, 1H), 7.19-7.31 (m, 3H), 7.42-7.53 (m, 4H), 8.04 (d,J=8.3 Hz, 1H), 10.1 (br, 1H). ESI-MS (m/z); 375 [M+H]⁺

EXAMPLE 85 (E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}homopiperazinedihydrochloride (Compound 85)

A solution of Compound 82 (100 mg, 0.224 mmol) in methanol (10.0 mL) wasadded with 10% hydrogen chloride-methanol solution (10.0 mL), followedby stirring at 60° C. for 2 hours. After cooling to room temperature,deposited crystal was collected by filtration to obtain Compound 85(48.7 mg, 47%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.00-2.18 (m, 2H), 3.21-3.32 (m, 4H),3.45-3.69 (m, 4H), 7.21 (t, J=7.3 Hz, 1H), 7.38 (t, J=8.3 Hz, 1H), 7.44(d, J=8.6 Hz, 2H), 7.53 (d, J=16.1 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.67(d, J=16.1 Hz, 1H), 7.78 (d, J=8.3 Hz, 2H), 8.19 (d, J=8.3 Hz, 1H), 9.37(br, 2H), 9.60 (br, 1H). ESI-MS (m/z); 347 [M+H]⁺

EXAMPLE 86(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperidine-4-carboxamide(Compound 86)

In a similar manner to Example 5, Compound 86 (89 mg, 22%) was obtainedusing Compound 50 (400 mg, 1.06 mmol), 1-hydroxybenzotriazolemonoammonium salt (400 mg, 1.6 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (307 mg, 1.6mmol) and N-methylmorpholine (0.350 mL, 3.18 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.47 (brs, 2H), 1.72 (brs, 2H), 2.49 (m,1H), 3.34 (brs, 2H), 3.45 (brs, 2H), 6.82 (brs, 1H), 7.21 (m, 1H), 7.31(brs, 2H), 7.39 (m, 2H), 7.59 (m, 3H), 7.76 (d, J=8.4 Hz, 2H), 8.19 (d,J=8.4 Hz, 1H), 13.2 (brs, 1H). ESI-MS (m/z); 375 [M+H]⁺

EXAMPLE 87(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-hydroxypiperidine(Compound 87)

In a similar manner to Example 5 Compound 87 (99.1 mg, 15%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg, 1.89 mmol),4-hydroxypiperidine (230 mg, 2.27 mmol), 1-hydroxybenzotriazolemonohydrate (434 mg, 2.84 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (543.5 mg,2.84 mmol) and N-methylmorpholine (0.623 mL, 5.67 mmol).

¹H-NMR (300 MHz, DMSO-d₆) δ 1.36 (brs, 2H), 1.74 (brs, 2H), 3.20 (brs,2H), 3.48 (brs, 2H), 3.73 (brs, 1H), 4.81 (br, 1H), 7.21 (m, 1H), 7.39(m, 3H), 7.55 (m, 3H), 7.76 (d, J=8.4 Hz, 2H), 8.19 (d, J=8.4 Hz, 1H).ESI-MS (m/z); 348 [M+H]⁺

EXAMPLE 88(E)-N-methyl-N-(2-oxo-2-morpholinoethyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 88)

Step 1

The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid(1.50 g, 5.68 mmol), sarcosine ethyl ester hydrochloride (1.05 g, 6.81mmol), 1-hydroxybenzotriazole monohydrate (1.31 g, 6.81 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.63 g,8.52 mmol) and N-methylmorpholine (1.87 mL, 17.0 mmol) in a similarmanner to Example 5, was neutralized by adding 2 mol/L aqueous sodiumhydroxide solution (20 ml), and the mixture was filtered to obtain(E)-N-methyl-N-carboxymethyl-4-[2-(1H-indazol-3-yl)vinyl]benzamide (1.04g, 55%).

Step 2

In a similar manner to Example 5, Compound 88 (218 mg, 61%) was obtainedusing (E)-N-methyl-N-carboxymethyl-4-[2-(1H-indazol-3-yl)vinyl]benzamide(300 mg, 0.89 mmol) obtained in Step 1, morpholine (0.093 mL, 1.07mmol), 1-hydroxybenzotriazole monohydrate (205 mg, 1.34 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (256 mg,1.34 mmol) and N-methylmorpholine (0.294 mL, 2.67 mmol).

¹H-NMR (300 MHz, DMSO-d₆) δ 2.94 (s, 3H), 3.20-3.60 (m, 8H), 4.33 (s,2H), 7.20 (m, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.36-7.45 (m, 2H), 7.53-7.60(m, 3H), 7.73-7.80 (m, 2H), 8.19 (d, J=8.3 Hz, 1H), 13.2 (s, 1H). ESI-MS(m/z); 405 [M+H]⁺

EXAMPLE 89 (E)-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperadin-2-one(Compound 89)

In a similar manner to Example 5, Compound 89 (309 mg, 60%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol)obtained in Step 6 of Example 1, piperadin-2-one (284 mg, 2.83 mmol),1-hydroxybenzotriazole monohydrate (332 mg, 2.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.67 mmol) and N-methylmorpholine (850 mL, 7.73 mmol).

¹H-NMR (300 MHz, DMSO-d₆) δ 3.20-3.28 (m, 2H), 3.55-3.64 (m, 2H),4.00-4.04 (brs, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.40 (t, J=7.3 Hz, 1H),7.47 (d, J=8.4 Hz, 2H), 7.52 (d, J=16.1 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H),7.68 (d, J=16.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 8.13 (br, 1H), 8.20 (d,J=8.1 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 347 [M+H]⁺

EXAMPLE 90(E)-4-(3-methyl-3-hydroxybutyryl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 90)

In a similar manner to Example 5, Compound 90 (204 mg, 66%) was obtainedusing dihydrochloride of Compound 18 (320 mg, 0.963 mmol),β-hydroxyisovaleric acid (85.0 mg, 0.718 mmol), 1-hydroxybenzotriazolemonohydrate (126 mg, 0.932 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg,1.01 mmol) and N-methylmorpholine (0.322 mL, 2.93 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.18 (s, 6H), 3.30 (s, 2H), 3.36-3.55 (m,8H), 4.76 (br, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.38 (t, J=7.3 Hz, 1H), 7.44(d, J=8.4 Hz, 2H), 7.51 (d, J=16.3 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.67(d, J=16.3 Hz, 1H), 7.79 (d, J=8.1 Hz, 2H), 8.20 (d, J=8.1 Hz, 1H), 13.2(br, 1H). ESI-MS (m/z); 433 [M+H]⁺

EXAMPLE 91(E)-N-(3-oxo-3-morpholinopropyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 91)

Step 1

Compound 79 (1.0 g, 2.75 mmol) was dissolved in THF (30 mL), and thesolution was added with 2 mol/L aqueous sodium hydroxide solution (20mL), followed by neutralization and filtration to obtain(E)-N-(2-carboxyethyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamide (710 mg,77%).

Step 2

In a similar manner to Example 5, Compound 91 (466 mg, 66%) was obtainedusing (E)-N-(2-carboxyethyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamide (300mg, 0.900 mmol), morpholine (0.094 mL, 1.07 mmol),1-hydroxybenzotriazole monohydrate (206 mg, 1.34 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (257 mg,1.34 mmol) and N-methylmorpholine (0.295 mL, 2.69 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.57-2.63 (m, 2H), 3.27-3.31 (m, 3H),3.36-3.39 (m, 4H), 3.44-3.55 (m, 4H), 7.21 (m, 1H), 7.39 (m, 1H),7.50-7.63 (m, 3H), 7.69-7.87 (m, 4H), 8.20 (d, J=8.1 Hz, 1H), 8.51 (m,1H). ESI-MS (m/z); 405 [M+H]⁺

EXAMPLE 92(E)-N,N-dimethyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperidine-4-carboxamide(Compound 92)

In a similar manner to Example 5, Compound 92 (27 mg, 5%) was obtainedusing Compound 50 (500 mg, 1.33 mmol), dimethylamine hydrochloride (230mg, 1.50 mmol), 1-hydroxybenzotriazole monohydrate (306 mg, 2.00 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (383 mg,2.00 mmol) and N-methylmorpholine (0.439 mL, 4.00 mmol).

¹H-NMR (300 MHz, DMSO-d₆) δ 1.43 (brs, 2H), 1.53 (brs, 2H), 2.80 (s,3H), 2.92 (brs, 2H), 3.02 (s, 3H), 3.20 (brs, 2H), 4.00 (brs, 1H), 4.44(brs, 1H), 7.20 (t, J=7.3 Hz, 1H), 7.38 (m, 3H), 7.55 (m, 3H), 7.76 (d,J=8.1 Hz, 2H), 8.19 (d, J=8.1 Hz, 1H), 13.2 (brs, 1H). ESI-MS (m/z); 403[M+H]⁺

EXAMPLE 93(E)-N-[2-(diethylcarbamoyl)ethyl]-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 93)

In a similar manner to Example 5, Compound 93 (119 mg, 24%) was obtainedusing (E)-N-(2-carboxyethyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamide (400mg, 1.25 mmol) obtained in Step 1 of Example 91, diethylamine (0.155 mL,1.5 mmol), 1-hydroxybenzotriazole monohydrate (287 mg, 1.88 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (359 mg,1.88 mmol) and N-methylmorpholine (0.041 mL, 3.7 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 0.91 (t, J=7.1 Hz, 3H), 0.98 (t, J=7.1 Hz,3H), 2.39 (s, 1H), 3.19 (dd, J=12.6, 6.9 Hz, 4H), 3.28 (m, 2H), 3.39(dd, J=12.9, 6.9 Hz, 2H), 7.08-7.14 (m, 1H), 7.27-7.33 (m, 1H),7.43-7.62 (m, 2H), 7.72 (dd, J=19.5, 8.3 Hz, 5H), 8.12 (d, J=8.1 Hz,1H), 8.42 (t, J=5.5 Hz, 1H), 13.1 (s, 1H). APCI-MS (m/z); 391 [M+H]⁺

EXAMPLE 94(E)-N-diethylcarbamoylmethyl-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 94)

In a similar manner to Example 5, Compound 94 (103 mg, 29%) was obtainedusing Compound 53 (300 mg, 0.932 mmol), diethylamine (123 mg, 1.12mmol), 1-hydroxybenzotriazole monohydrate (214 mg, 1.40 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (268 mg,1.40 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.02 (t, J=7.0 Hz, 3H), 1.16 (t, J=7.0 Hz,3H), 3.27-3.36 (m, 4H), 4.10 (d, J=5.5 Hz, 2H), 7.21 (m, 1H), 7.39 (m,1H), 7.53-7.71 (m, 3H), 7.86 (dd, J=26.4, 8.1 Hz, 4H), 8.20 (d, J=8.1Hz, 1H), 8.57 (s, 1H), 13.2 (s, 1H). ESI-MS (m/z); 377 [M+H]⁺

EXAMPLE 95(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]-2-methylbenzoyl}piperazinedihydrochloride (Compound 95)

Step 1

In a similar manner to Example 5,(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]-2-methylbenzoyl}piperazine-1-carboxylicacid 1,1-dimethylethyl ester (980 mg, 66%) was obtained using(E)-4-[2-(1H-indazol-3-yl)vinyl]-2-methylbenzoic acid (970 mg, 3.32mmol), N-(1,1-dimethylethoxycarbonyl)piperazine (926 mg, 4.98 mmol),1-hydroxybenzotriazole monohydrate (661 mg, 4.32 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (891 mg,4.65 mmol).

¹H-NMR (270 MHz, CDCl₃) δ 1.57 (s, 9H), 2.36 (s, 3H), 3.24-3.28 (br,2H), 3.36-3.38 (br, 2H), 3.50-3.56 (br, 2H), 3.76-3.82 (br, 2H), 7.18(d, J=5.1 Hz, 1H), 7.23-7.32 (m, 2H), 7.44-7.49 (m, 5H), 8.04 (d, J=8.2Hz, 1H), 10.1 (br, 1H). ESI-MS (m/z); 447 [M+H]⁺

Step 2

(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]-2-methylbenzoyl}piperazine-1-carboxylicacid 1,1-dimethylethyl ester (980 mg, 2.20 mmol) obtained in Step 1, wastreated with 10% hydrogen chloride-methanol solution to obtain Compound95 (585 mg, 77%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.26 (s, 3H), 3.04-3.41 (br, 4H), 3.55-3.60(br, 4H), 7.14-7.64 (m, 8H), 8.18 (d, J=8.2 Hz, 1H), 9.35-9.45 (br, 2H).ESI-MS (m/z); 347 [M+H]⁺

EXAMPLE 96(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-1-methylpiperazin-2-one(Compound 96)

In a similar manner to Example 5, Compound 96 (198 mg, 46%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (400 mg, 1.19 mmol)obtained in Step 6 of Example 1, 1-methylpiperazin-2-one (780 mg, 5.18mmol), 1-hydroxybenzotriazole monohydrate (210 mg, 1.55 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (320 mg,1.70 mmol) and N-methylmorpholine (0.70 mL, 6.37 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.87 (s, 3H), 3.37-3.39 (m, 2H), 3.60-3.82(brm, 2H), 4.03-4.09 (m, 2H), 7.21 (t, J=7.6 Hz, 1H), 7.39 (t, J=7.6 Hz,1H), 7.47 (d, J=8.2 Hz, 2H), 7.51 (d, J=16.1 Hz, 1H), 7.56 (d, J=8.1 Hz,1H), 7.68 (d, J=16.1 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 8.20 (d, J=8.1 Hz,1H), 13.2 (br, 1H). ESI-MS (m/z); 360 [M+H]⁺

EXAMPLE 97(E)-N-(3-morpholinopropyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamidedihydrochloride (Compound 97)

The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoicacid (500 mg, 1.89 mmol) obtained in Step 6 of Example 1,N-(3-aminopropyl)morpholine (0.365 mL, 2.50 mmol),1-hydroxybenzotriazole monohydrate (333 mg, 2.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg,2.67 mmol) and N-methylmorpholine (0.75 mL, 6.82 mmol) in a similarmanner to Example 5, was purified by silica gel column chromatography(hexane/ethyl acetate) to obtain a free base of Compound 97. Then thefree base of Compound 97 was dissolved in ethyl acetate (5.00 mL), andthe solution was added with 4 moL/L hydrogen chloride-ethyl acetatesolution (1.00 mL), followed by stirring at room temperature for 30minutes. The precipitate in the reaction mixture was filtered to obtainCompound 97 (340 mg, 78%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.98 (br, 2H), 3.03-3.12 (m, 4H), 3.34-3.44(m, 4H), 3.73-3.97 (m, 4H), 7.21 (t, J=7.4 Hz, 1H), 7.40 (t, J=7.4 Hz,1H), 7.55 (d, J=16.7 Hz, 1H), 7.56 (d, J=7.4 Hz, 1H), 7.68 (d, J=16.7Hz, 1H), 7.81 (d, J=7.4 Hz, 2H), 7.90 (d, J=7.4 Hz, 2H), 8.21 (d, J=7.4Hz, 1H), 8.71 (br, 1H). ESI-MS (m/z); 391 [M+H]⁺

EXAMPLE 98(E)-4-(3-methoxypropionyl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 98)

In a similar manner to Example 5, Compound 98 (220 mg, 59%) was obtainedusing dihydrochloride of Compound 18 (400 mg, 0.99 mmol),β-3-methoxypropionic acid (84.4 mg, 0.82 mmol), 1-hydroxybenzotriazolemonohydrate (178 mg, 1.32 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg,1.38 mmol) and N-methylmorpholine (0.4 mL, 1.64 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.58 (t, J=6.2 Hz, 2H), 3.22 (s, 3H),3.26-3.29 (m, 2H), 3.52-3.57 (m, 8H), 7.21 (t, J=7.7 Hz, 1H), 7.38 (d,J=8.2 Hz, 1H), 7.44, (d, J=8.2 Hz, 2H), 7.54 (d, J=16.8 Hz, 1H), 7.55(d, J=8.2 Hz, 1H), 7.64 (d, J=16.8 Hz, 1H), 7.79 (d, J=8.2 Hz, 2H), 8.20(d, J=8.2 Hz, 1H), 13.2 (br, 1H). APCI-MS (m/z); 419 [M+H]⁺

EXAMPLE 99(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(morpholinocarbonylamino)piperidine(Compound 99)

Compound 64 (500 mg, 1.19 mmol) was dissolved in dichloromethane, andthe solution was added with triethylamine (0.498 mL, 3.57 mmol),4-morpholinecarbonyl chloride (468 mg, 2.62 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (200.2 mg,1.04 mmol) at 0° C., followed by stirring for 4 hours to obtain Compound99 (1.5 mg, 0.3%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.37 (brs, 4H), 1.77 (brs, 4H), 3.18-3.53(m, 9H), 6.30 (d, J=7.1 Hz, 1H), 7.20-7.23 (m, 1H), 7.35-7.42 (m, 3H),7.53-7.65 (m, 4H), 7.76 (d, J=7.9 Hz, 2H), 8.18 (d, J=8.1 Hz, 1H).APCI-MS (m/z); 460 [M+H]⁺

EXAMPLE 100(E)-4-(2-methoxyacetyl)-1-{4-[2-(1H-indazol-3-yl)vinyl]-2-methylbenzoyl}piperazine(Compound 100)

A solution of methoxyacetic acid (0.019 mL, 0.24 mmol) in THF (5.0 mL)was added with Compound 95 (0.10 g, 0.29 mmol), 1-hydroxybenzotriazolemonohydrate (52 mg, 0.337 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg, 0.36mmol), followed by stirring at 60° C. for 1 hour. The reaction mixturewas added with ethyl acetate and saturated aqueous sodiumhydrogencarbonate solution (4.0 mL) and was extracted. The organic layerwas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/methanol=10/1), and theproduct was added with ethyl acetate, then precipitate was collected byfiltration to obtain Compound 100 (39 mg, 39%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.27 (s, 3H), 3.19 (brs, 2H), 3.29 (brs,3H), 3.37 (brs, 2H), 3.51 (brs, 2H), 4.10 (brd, 2H), 7.21 (t, J=6.6 Hz,1H), 7.22 (d, J=7.9 Hz, 1H), 7.40 (t, J=6.6 Hz, 1H), 7.49 (d, J=16.6 Hz,1H), 7.60 (d, J=16.6 Hz, 1H), 7.67-7.50 (m, 3H), 8.19 (d, J=8.4 Hz, 1H),13.18 (s, 1H) APCI-MS (m/z); 419 [M+H]⁺

EXAMPLE 101(S)-(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-3-methylpiperazinedihydrochloride (Compound 101)

In a similar manner to Example 5, a free base of Compound 101 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (250 mg,0.83 mmol) obtained in Step 6 of Example 1, (S)-(+)-2-methylpiperazine(170 mg, 1.66 mmol), 1-hydroxybenzotriazole monohydrate (217 mg, 1.60mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (303mg, 1.58 mmol) and N-methylmorpholine (0.23 mL, 2.08 mmol), then thefree base of Compound 101 was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 101 (158 mg,45%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.26 (br, 3H), 2.75 (br, 1H), 3.05-3.34 (m,6H), 7.22 (dd, J=7.9, 7.9 Hz, 1H), 7.40 (dd, J=7.9, 7.9 Hz, 1H), 7.49(d, J=8.3 Hz, 2H), 7.54 (d, J=8.3 Hz, 1H), 7.55 (d, J=16.8 Hz, 1H), 7.66(d, J=16.1 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 8.21 (d, J=8.3 Hz, 1H),9.47-9.51 (m, 1H), 9.65 (br, 1H). APCI-MS (m/z); 347 [M+H]⁺

EXAMPLE 102(R)-(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-3-methylpiperazinedihydrochloride (Compound 102)

In a similar manner to Example 5, a free base of Compound 102 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (250 mg,0.83 mmol) obtained in Step 6 of Example 1, (R)-(+)-2-methylpiperazine(170 mg, 1.66 mmol), 1-hydroxybenzotriazole monohydrate (217 mg, 1.60mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (303mg, 1.58 mmol) and N-methylmorpholine (0.23 mL, 2.08 mmol), then thefree base of Compound 102 was dissolved in methanol (2.00 mL) and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 102 (50 mg,14%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.26 (br, 3H), 2.75 (br, 1H), 3.09-3.45 (m,6H), 7.22 (dd, J=7.9, 7.9 Hz, 1H), 7.40 (dd, J=7.9, 7.9 Hz, 1H), 7.49(d, J=8.3 Hz, 2H), 7.54 (d, J=8.3 Hz, 1H), 7.55 (d, J=16.8 Hz, 1H), 7.66(d, J=16.1 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 8.21 (d, J=8.3 Hz, 1H),9.47-9.51 (m, 1H), 9.65 (br, 1H). APCI-MS (m/z); 347 [M+H]⁺

EXAMPLE 103(S*,S*)-(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-3,5-dimethylpiperazinedihydrochloride (Compound 103)

In a similar manner to Example 5, a free base of Compound 103 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (250 mg,0.83 mmol) obtained in Step 6 of Example 1, 2,6-dimethylpiperazine (243mg, 1.66 mmol), 1-hydroxybenzotriazole monohydrate (217 mg, 1.60 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (303 mg,1.58 mmol) and N-methylmorpholine (0.23 mL, 2.08 mmol), then the freebase of Compound 103 was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 103 (140 mg,51%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.28 (br, 6H), 3.03-3.33 (br, 4H), 4.5 (br,2H), 7.24 (dd, J=8.3, 8.3 Hz, 1H), 7.41 (dd, J=8.3, 8.3 Hz, 1H), 7.50(d, J=8.3 Hz, 2H), 7.54 (d, J=8.3 Hz, 1H), 7.56 (d, J=16.7 Hz, 1H), 7.66(d, J=16.7 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 8.21 (d, J=8.3 Hz, 1H),9.48-9.51 (m, 1H), 9.87-9.90 (m, 1H). APCI-MS (m/z); 361 [M+H]⁺

EXAMPLE 104(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-ethylpiperazinedihydrochloride (Compound 104)

In a similar manner to Example 5, a free base of Compound 104 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg,1.00 mmol) obtained in Step 6 of Example 1, N-ethylpiperazine (171 mg,1.50 mmol), 1-hydroxybenzotriazole monohydrate (176 mg, 1.30 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg,1.40 mmol)-and N-methylmorpholine (0.22 mL, 2.00 mmol), then the freebase of Compound 104 was dissolved in methanol (2.00 mL) and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 104 (280 mg,65%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.27 (t, J=7.4 Hz, 3H), 3.03-3.14 (m, 4H),3.46 (br, 2H), 4.54 (br, 4H), 7.22 (dd, J=7.4, 7.4 Hz, 1H), 7.41 (dd,J=7.4, 7.4 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.54 (d, J=7.4 Hz, 1H), 7.56(d, J=16.7 Hz, 1H), 7.67 (d, J=16.7 Hz, 1H), 7.81 (d, J=8.2 Hz, 2H),8.21 (d, J=8.2 Hz, 1H), 11.2 (br, 1H). APCI-MS (m/z); 361 [M+H]⁺

EXAMPLE 105(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(2-hydroxyethyl)piperazine(Compound 105)

In a similar manner to Example 5, Compound 105 (230 mg, 61%) wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg,1.00 mmol) obtained in Step 6 of Example 1, 2-(piperazin-1-yl)ethanol(195 mg, 1.50 mmol), 1-hydroxybenzotriazole monohydrate (176 mg, 1.30mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270mg, 1.40 mmol) and N-methylmorpholine (0.22 mL, 2.00 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.41-2.49 (m, 8H), 3.48-3.55 (m, 4H), 4.43(t, J=5.4 Hz, 1H), 7.23 (dd, J=8.1, 8.1 Hz, 1H), 7.18-7.28 (m, 1H), 7.23(d, J=8.1 Hz, 2H), 7.54 (d, J=16.1 Hz, 1H), 7.57 (d, J=16.7 Hz, 1H),7.67 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.1 Hz, 2H), 8.20 (d, J=8.1 Hz, 1H),13.2 (br, 1H). APCI-MS (m/z); 377 [M+H]⁺

EXAMPLE 106(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-morpholinopiperidine(Compound 106)

In a similar manner to Example 5, Compound 106 (319 mg, 77%) wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg,1.00 mmol) obtained in Step 6 of Example 1, 4-morpholinopiperidine (255mg, 1.50 mmol), 1-hydroxybenzotriazole monohydrate (176 mg, 1.30 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg,1.40 mmol) and N-methylmorpholine (0.22 mL, 2.00 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.31-1.43 (m, 2H), 1.81 (br, 2H), 2.38 (br,2H), 2.42 (br, 4H), 2.86-3.00 (m, 2H), 3.55-3.58 (m, 4H), 4.44 (br, 1H),7.22 (dd, J=7.9, 7.9 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.41 (d, J=8.3 Hz,2H), 7.57 (d, J=16.8 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.64 (d, J=16.8Hz, 1H), 7.78 (d, J=8.3 Hz, 2H), 8.21 (d, J=8.3 Hz, 1H), 13.2 (br, 1H).APCI-MS (m/z); 417 [M+H]⁺

EXAMPLE 107(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-isopropylpiperazinehydrochloride (Compound 107)

In a similar manner to Example 5, a free base of Compound 107 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg,1.00 mmol) obtained in Step 6 of Example 1, 1-isopropylpiperazine (192mg, 1.50 mmol), 1-hydroxybenzotriazole monohydrate (176 mg, 1.30 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg,1.40 mmol) and N-methylmorpholine (0.22 mL, 2.00 mmol), then the freebase of Compound 107 was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 107 (24.5 mg,5.5%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.28 (d, J=6.8 Hz, 6H), 3.15 (br, 1H),3.33-3.41 (m, 8H), 7.23 (dd, J=7.9, 7.9 Hz, 1H), 7.41 (dd, J=8.3, 8.3Hz, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.61 (d, J=16.7Hz, 1H), 7.67 (d, J=16.7 Hz, 1H), 7.82 (d, J=8.3 Hz, 2H), 8.21 (d, J=8.3Hz, 1H), 10.0 (br, 1H). ESI-MS (m/z); 375 [M+H]⁺

EXAMPLE 108(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-[2-(dimethylamino)ethyl]piperazine,dihydrochloride (Compound 108)

In a similar manner to Example 5, a free base of Compound 108 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg,1.00 mmol) obtained in Step 6 of Example 1,1-(2-dimethylaminoethyl)piperazine (235 mg, 1.50 mmol),1-hydroxybenzotriazole monohydrate (176 mg, 1.30 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg,1.40 mmol) and N-methylmorpholine (0.22 mL, 2.00 mmol), then the freebase of Compound 108 was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 108 (144 mg,30%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.86 (s, 6H), 3.17-3.53 (m, 12H), 7.23 (dd,J=7.8, 7.8 Hz, 1H), 7.40 (dd, J=7.8, 7.8 Hz, 1H), 7.51 (d, J=8.3 Hz,2H), 7.57 (d, J=8.3 Hz, 1H), 7.61 (d, J=16.7 Hz, 1H), 7.68 (d, J=16.7Hz, 1H), 7.83 (d, J=8.3 Hz, 2H), 8.21 (d, J=8.3 Hz, 1H), 10.0 (br, 1H).ESI-MS (m/z); 404 [M+H]⁺

EXAMPLE 109(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(2-methoxyethyl)piperazinehydrochloride (Compound 109)

(1H-indazol-3-ylmethyl)triphenylphosponioum bromide (473 mg, 1.00 mmol)was dissolved in methanol (10 mL), then a free base of Compound 109 wasobtained using 4-[4-(2-methoxyethyl)piperazine-1-carbonyl]benzaldehyde(230 g, 0.83 mmol) and potassium carbonate (345 mg, 2.50 mmol). The freebase of Compound 109 was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 109 (178 mg,38%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.13-3.17 (m, 2H), 3.32 (s, 3H), 3.46 (br,8H), 3.70-3.74 (m, 2H), 7.22 (dd, J=7.9, 7.9 Hz, 1H), 7.41 (dd, J=7.9,7.9 Hz, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.56 (d, J=16.8 Hz, 1H), 7.57 (d,J=8.2 Hz, 1H), 7.67 (d, J=16.8 Hz, 1H), 7.82 (d, J=8.2 Hz, 2H), 8.21 (d,J=8.2 Hz, 1H), 10.0 (br, 1H). APCI-MS (m/z); 391 [M+H]⁺

EXAMPLE 110(E)-N-[2-(ethylamino)ethyl]-4-[2-(1H-indazol-3-yl)vinyl]benzamide(Compound 110)

In a similar manner to Example 5, Compound 110 (40 mg, 12%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg, 1.00 mmol)obtained in Step 6 of Example 1, N-ethylethylenediamine (440 mg, 5.00mmol), 1-hydroxybenzotriazole monohydrate (176 mg, 1.30 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg,1.40 mmol) and N-methylmorpholine (0.22 mL, 2.00 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.03 (t, J=7.1 Hz, 3H), 2.52-2.60 (m, 2H),2.68 (t, J=6.6 Hz, 2H), 3.32-3.36 (m, 3H), 7.22 (dd, J=7.1, 7.1 Hz, 1H),7.41 (dd, J=7.1, 7.1 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.57 (d, J=16.6Hz, 1H), 7.68 (d, J=16.6 Hz, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.3Hz, 2H), 8.22 (d, J=8.3 Hz, 1H), 8.40 (t, J=8.3 Hz, 1H), 13.2 (br, 1H).APCI-MS (m/z); 335 [M+H]⁺

EXAMPLE 111 (E)-N-(2-aminoethyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamidedihydrochloride (Compound 111)

The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid(300 mg, 1.00 mmol) obtained in Step 6 of Example 1,N-(2-aminoethyl)carbamic acid tert-butyl ester (240 mg, 1.50 mmol),1-hydroxybenzotriazole monohydrate (176 mg, 1.30 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg,1.40 mmol) and N-methylmorpholine (0.22 mL, 2.00 mmol) in a similarmanner to Example 5, was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by heating under reflux at 60° C. for 30 minutes.The reaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 111 (206 mg,54%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.98-3.04 (m, 2H), 3.52-3.57 (m, 2H), 7.23(dd, J=7.9, 7.9 Hz, 1H), 7.41 (dd, J=7.9, 7.9 Hz, 1H), 7.56 (d, J=8.3Hz, 1H), 7.57 (d, J=16.7 Hz, 1H), 7.70 (d, J=16.7 Hz, 1H), 7.83 (d,J=8.3 Hz, 2H), 7.95 (d, J=8.3 Hz, 2H), 8.04 (br, 2H), 8.22 (d, J=8.3 Hz,1H), 8.76 (t, J=5.3 Hz, 1H). ESI-MS (m/z); 307 [M+H]⁺

EXAMPLE 112(E)-N-[2-(methylamino)ethyl]-4-[2-(1H-indazol-3-yl)vinyl]benzamidehydrochloride (Compound 112)

In a similar manner to Example 5, a free base of Compound 112 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg,1.00 mmol) obtained in Step 6 of Example 1, N-methylethylenediamine (111mg, 1.50 mmol), 1-hydroxybenzotriazole monohydrate (176 mg, 1.30 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg,1.40 mmol) and N-methylmorpholine (0.22 mL, 2.00 mmol), then the freebase of Compound 112 was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 112 (105 mg,29%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.58-2.61 (m, 3H), 3.11 (br, 2H), 3.56-3.63(m, 2H), 7.23 (dd, J=7.9, 7.9 Hz, 1H), 7.41 (dd, J=8.3, 8.3 Hz, 1H),7.56 (d, J=8.3 Hz, 1H), 7.57 (d, J=16.8 Hz, 1H), 7.70 (d, J=16.8 Hz,1H), 7.83 (d, J=8.3 Hz, 2H), 7.96 (d, J=8.3 Hz, 2H), 8.22 (d, J=8.3 Hz,1H), 8.80-8.84 (m, 2H). APCI-MS (m/z); 321 [M+H]⁺

EXAMPLE 113(E)-1-methoxyacetyl-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}homopiperazine(Compound 113)

In a similar manner to Example 5, Compound 113 (98 mg, 35%) was obtainedusing Compound 85 (285 mg, 0.68 mmol), methoxyacetic acid (0.05 ml, 0.62mmol), 1-hydroxybenzotriazole monohydrate (110 mg, 0.81 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg,0.87 mmol) and N-methylmorpholine (0.34 mL, 3.10 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.22-3.77 (m, 13H), 4.11 (br, 2H), 7.22 (dd,J=7.1, 7.1 Hz, 1H), 7.35-7.43 (m, 3H), 7.54 (d, J=16.8 Hz, 1H), 7.56 (d,J=8.4 Hz, 1H), 7.64 (d, J=16.8 Hz, 1H), 7.78 (d, J=8.1 Hz, 2H), 8.21 (d,J=8.1 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 419 [M+H]⁺

EXAMPLE 114(E)-1-(3-methyl-3-hydroxybutyryl)-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}homopiperazine(Compound 114)

In a similar manner to Example 5, Compound 114 (62 mg, 20%) was obtainedusing Compound 85 (285 mg, 0.68 mmol), β-hydroxyisovaleric acid (73 mg,0.62 mmol), 1-hydroxybenzotriazole monohydrate (110 mg, 0.81 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg,0.87 mmol) and N-methylmorpholine (0.34 mL, 3.10 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.12-1.19 (m, 6H), 1.91 (br, 1H), 3.53 (br,12H), 7.22 (dd, J=7.4, 7.4 Hz, 1H), 7.32-7.44 (m, 3H), 7.54 (d, J=16.8Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.64 (d, J=16.8 Hz, 1H), 7.78 (d, J=8.4Hz, 2H), 8.21 (d, J=8.4 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 447 [M+H]⁺

EXAMPLE 115(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-1-(n-propyl)piperazin-2-onehydrochloride (Compound 115)

In a similar manner to Example 5, a free base of Compound 115 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (260 mg,0.87 mmol) obtained in Step 6 of Example 1, 1-n-propylpiperazin-2-one(309 mg, 1.74 mmol), 1-hydroxybenzotriazole monohydrate (153 mg, 1.13mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (234mg, 1.22 mmol) and N-methylmorpholine (0.50 mL, 4.35 mmol), then thefree base of Compound 115 was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 115 (240 mg,65%).

¹H-NMR (270 MHz, DMSO-d₆) δ 0.83 (t, J=7.4 Hz, 3H), 3.26-3.63 (m, 6H),3.73 (br, 2H), 4.11 (br, 2H), 7.22 (dd, J=7.1, 7.1 Hz, 1H), 7.41 (dd,J=7.8, 7.8 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.53 (d, J=7.1 Hz, 1H), 7.55(d, J=16.7 Hz, 1H), 7.66 (d, J=16.7 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H),8.21 (d, J=8.4 Hz, 1H). APCI-MS (m/z); 389 [M+H]⁺

EXAMPLE 116(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-1-(sec-butyl)piperazin-2-onehydrochloride (Compound 116)

In a similar manner to Example 5, a free base of Compound 116 wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (128 mg,0.42 mmol) obtained in Step 6 of Example 1, 1-sec-butylpiperazin-2-one(121 mg, 0.63 mmol), 1-hydroxybenzotriazole monohydrate (75 mg, 0.55mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115mg, 0.59 mmol) and N-methylmorpholine (0.24 mL, 2.10 mmol), then thefree base of Compound 116 was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 116 (74 mg,40%).

¹H-NMR (270 MHz, DMSO-d₆) δ 0.78 (t, J=7.3 Hz, 3H), 1.05 (d, J=6.9 Hz,3H), 1.34-1.47 (m, 2H), 3.23-3.32 (m, 1H), 4.39 (br, 6H), 7.21 (dd,J=8.1, 8.1 Hz, 1H), 7.40 (dd, J=8.1, 8.1 Hz, 1H), 7.48 (d, J=8.1 Hz,2H), 7.53 (d, J=16.7 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.65 (d, J=16.7Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 8.20 (d, J=8.1 Hz, 1H). APCI-MS (m/z);403 [M+H]⁺

EXAMPLE 117(E)-1-{4-[2-(1H-indazol3-yl)vinyl]benzoyl}-1,2,3,6-tetrahydropyridine(Compound 117)

In a similar manner to Example 5, Compound 117 (196 mg, 72%) wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (250 mg,0.83 mmol) obtained in Step 6 of Example 1, 1,2,3,6-tetrahydropyridine(0.11 ml, 1.25 mmol), 1-hydroxybenzotriazole monohydrate (146 mg, 1.08mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (224mg, 1.16 mmol) and N-methylmorpholine (0.18 mL, 1.66 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.15 (br, 2H), 3.44-4.03 (m, 4H), 5.74-5.88(m, 2H), 7.21 (dd, J=7.1, 7.1 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.40-7.43(m, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.54 (d, J=16.6 Hz, 1H), 7.63 (d,J=16.6 Hz, 1H), 7.77 (d, J=8.1 Hz, 2H), 8.20 (d, J=8.1 Hz, 1H), 13.2(br, 1H). APCI-MS (m/z); 330 [M+H]⁺

EXAMPLE 118(S)-(E)-4-methoxyacetyl-3-methyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinehydrochloride (Compound 118)

In a similar manner to Example 5, a free base of Compound 118 wasobtained using Compound 101 (300 mg, 0.72 mmol), methoxyacetic acid(0.05 ml, 0.62 mmol), 1-hydroxybenzotriazole monohydrate (106 mg, 0.81mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161mg, 0.87 mmol) and N-methylmorpholine (0.34 mL, 3.10 mmol), then thefree base of Compound 118 was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 118 (87 mg,27%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.08-1.15 (m, 3H), 3.29 (s, 3H), 4.04 (br,9H), 7.22 (dd, J=7.4, 7.4 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.38-7.45 (m,1H), 7.53 (d, J=8.4 Hz, 1H), 7.55 (d, J=16.6 Hz, 1H), 7.65 (d, J=16.6Hz, 1H), 7.80 (d, J=8.4 Hz, 2H), 8.21 (d, J=8.4 Hz, 1H). APCI-MS (m/z);419 [M+H]⁺

EXAMPLE 119(S)-(E)-4-(3-methyl-3-hydroxybutyryl)-3-methyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinehydrochloride (Compound 119)

In a similar manner to Example 5, a free base of Compound 119 wasobtained using Compound 101 (500 mg, 1.19 mmol), β-hydroxyisovalericacid (0.12 mg, 0.99 mmol), 1-hydroxybenzotriazole monohydrate (174 mg,1.29 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(270 mg, 1.39 mmol) and N-methylmorpholine (0.50 mL, 4.46 mmol), thenthe free base of Compound 119 was dissolved in methanol (2.00 mL), andthe solution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 119 (237 mg,41%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.04-1.18 (m, 9H), 2.30 (br, 1H), 4.02 (br,9H), 7.22 (dd, J=7.9, 7.9 Hz, 1H), 7.39 (d, J=8.2 Hz, 2H), 7.38-7.46 (m,1H), 7.53 (d, J=8.2 Hz, 1H), 7.55 (d, J=16.6 Hz, 1H), 7.65 (d, J=16.6Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 8.21 (d, J=8.2 Hz, 1H). APCI-MS (m/z);447 [M+H]⁺

EXAMPLE 120 (E)-4-[2-(1H-indazol-3-yl)vinyl]-N-(piperidin-4-yl)benzamidedihydrochloride (Compound 120)

The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid(500 mg, 1.66 mmol) obtained in Step 6 of Example 1,1-tert-butoxycarbonyl-4-aminopiperidine (500 mg, 2.49 mmol),1-hydroxybenzotriazole monohydrate (291 mg, 2.16 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (450 mg,2.32 mmol) and N-methylmorpholine (0.37 mL, 3.32 mmol) in a similarmanner to Example 5, was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by heating under reflux at 60° C. for 30 minutes.The reaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 120 (337 mg,48%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.78-1.85 (m, 2H), 1.96-2.09 (m, 2H),3.00-3.03 (m, 2H), 3.30-3.34 (m, 2H), 4.07 (br, 1H), 7.22 (dd, J=7.2,7.2 Hz, 1H), 7.41 (dd, J=8.4, 8.4 Hz, 1H), 7.56 (d, J=16.8 Hz, 1H), 7.73(d, J=16.8 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 8.22(d, J=8.4 Hz, 1H), 8.50 (d, J=7.2 Hz, 1H), 8.86 (br, 1H). APCI-MS (m/z);347 [M+H]⁺

EXAMPLE 121(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-[2-oxo-2-(pyrrolidin-1-yl)ethyl]piperazine(Compound 121)

The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoicacid (300 mg, 1.14 mmol) obtained in Step 6 of Example 1,N-methylmorpholine (0.25 mL, 2.28 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (305 mg,1.59 mmol), 1-hydroxybenzotriazole monohydrate (200 mg, 1.48 mmol) and2-(piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone (337 mg, 1.71 mmol) in asimilar manner to Step 7 of example 1, was triturated in mixed solventof ethyl acetate/methanol to obtain Compound 121 (298 mg, 60%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.72-1.91 (m, 4H), 3.28 (t, J=6.5 Hz, 2H),3.45 (t, J=6.5 Hz, 2H), 3.40-7.70 (br, 8H), 7.22 (t, J=7.8 Hz, 1H), 7.38(t, J=7.8 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.54 (d, J=16.7 Hz, 1H), 7.56(d, J=8.4 Hz, 1H), 7.64 (d, J=16.7 Hz, 1H), 7.78 (d, J=8.1 Hz, 2H), 8.21(d, J=8.4 Hz, 1H), 13.22 (s, 1H). APCI-MS (m/z); 444 [M]⁺

EXAMPLE 122(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-3-aminopyrrolidinedihydrochloride (Compound 122)

The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid(800 mg, 2.66 mmol) obtained in Step 6 of Example 1,(pyrrolidin-3-yl)carbamic acid tert-butyl ester (1.00 g, 5.32 mmol),1-hydroxybenzotriazole monohydrate (470 mg, 3.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (720 mg,3.72 mmol) and N-methylmorpholine (0.58 mL, 5.32 mmol) in a similarmanner to Example 5, was dissolved in methanol (5.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(2.00 mL), followed by heating under reflux at 60° C. for 1 hour. Thereaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 122 (398 mg,38%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.23 (br, 1H), 3.54-3.87 (m, 6H), 7.22 (dd,J=7.7, 7.7 Hz, 1H), 7.41 (dd, J=7.7, 7.7 Hz, 1H), 7.54 (d, J=8.3 Hz,2H), 7.55 (d, J=8.3 Hz, 1H), 7.57 (d, J=16.8 Hz, 1H), 7.66 (d, J=16.8Hz, 1H), 7.80 (d, J=8.3 Hz, 2H), 8.21 (d, J=8.3 Hz, 1H), 8.30 (br, 1H),8.42 (br, 1H). APCI-MS (m/z); 333 [M+H]⁺

EXAMPLE 123(S)-(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(2-amino-3-hydroxypropionyl)piperazinedihydrochloride (Compound 123)

The product obtained using Compound 18 (300 mg, 0.90 mmol),N-(tert-butoxycarbonyl)-L-serine (155 mg, 0.76 mmol),1-hydroxybenzotriazole monohydrate (133 mg, 0.99 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (204 mg,1.06 mmol) and N-methylmorpholine (0.17 mL, 1.52 mmol) in a similarmanner to Example 5, was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by heating under reflux at 60° C. for 30 minutes.The reaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 123 (290 mg,78%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.63-3.73 (m, 8H), 4.43 (br, 1H), 4.95 (br,3H), 7.22 (dd, J=7.7, 7.7 Hz, 1H), 7.41 (dd, J=8.2, 8.2 Hz, 1H), 7.48(d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 1H), 7.56 (d, J=16.8 Hz, 1H), 7.66(d, J=16.8 Hz, 1H), 7.81 (d, J=8.2 Hz, 2H), 8.20-8.23 (m, 3H). APCI-MS(m/z); 420 [M+H]⁺

EXAMPLE 124(S)-(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(pyrrolidin-3-ylcarbonyl)piperazinedihydrochloride (Compound 124)

The product obtained using Compound 18 (300 mg, 0.90 mmol),(S)-pyrrolidin-1,3-dicarboxylic acid 1-tert-butyl ester (162 mg, 0.76mmol), 1-hydroxybenzotriazole monohydrate (133 mg, 0.99 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (204 mg,1.06 mmol) and N-methylmorpholine (0.17 mL, 1.52 mmol) in a similarmanner to Example 5, was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by heating under reflux at 60° C. for 30 minutes.The reaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 124 (278 mg,61%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.78-1.94 (m, 2H), 2.40 (br, 1H), 3.15-3.26(m, 2H), 3.58 (br, 8H), 4.60 (br, 2H), 7.22 (dd, J=7.1, 7.1 Hz, 1H),7.41 (dd, J=8.2, 8.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz,1H), 7.56 (d, J=16.6 Hz, 1H), 7.66 (d, J=16.6 Hz, 1H), 7.82 (d, J=8.2Hz, 2H), 8.21 (d, J=8.2 Hz, 1H), 8.50 (br, 1H) 9.96-9.98 (m, 1H).APCI-MS (m/z); 430 [M+H]⁺

EXAMPLE 125(E)-4-dimethylaminoacetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 125)

In a similar manner to Example 5, Compound 125 (77 mg, 31%) was obtainedusing Compound 18 (200 mg, 0.60 mmol), N,N-dimethylglycine (70 mg, 0.50mmol), 1-hydroxybenzotriazole monohydrate (88 mg, 0.65 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg,0.70 mmol) and N-methylmorpholine (0.11 mL, 1.00 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.17 (s, 6H), 3.08 (br, 2H), 3.50-3.58 (m,8H), 7.21 (dd, J=7.1, 7.1 Hz, 1H), 7.37-7.46 (m, 1H), 7.47 (d, J=8.2 Hz,2H), 7.52 (d, J=8.2 Hz, 1H), 7.54 (d, J=16.6 Hz, 1H), 7.64 (d, J=16.6Hz, 1H), 7.79 (d, J=8.1 Hz, 2H), 8.20 (d, J=8.2 Hz, 1H), 13.2 (br, 1H).APCI-MS (m/z); 418 [M+H]⁺

EXAMPLE 126(E)-4-[(isobutyrylamino)acetyl]-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 126)

The crude product (174 mg) obtained using Compound 18 (200 mg, 0.602mmol), N-methylmorpholine (0.132 mL, 1.20 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg,0.842 mmol), 1-hydroxybenzotriazole monohydrate (106 mg, 0.783 mmol) and(3-methylbutyrylamino)acetic acid (115 mg, 0.722 mmol) in a similarmanner to Example 5, was purified by silica gel column chromatography(chloroform/methanol=80/20), followed by triturating in mixed solvent ofethyl acetate/ethanol to obtain Compound 126 (105 mg, 37%).

¹H-NMR (300 MHz, DMSO-d₆) δ 0.89 (d, J=6.0 Hz, 6H), 1.90-2.08 (m, 3H),3.25-3.75 (br, 8H), 3.80-4.04 (br.s, 2H), 7.22 (t, J=6.9 Hz, 1H), 7.41(t, J=6.9 Hz, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.56 (d, J=16.8 Hz, 1H), 7.57(d, J=7.8 Hz, 1H), 7.66 (d, J=16.8 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.91(br, 1H), 8.21 (d, J=7.8 Hz, 1H), 13.22 (s, 1H). APCI-MS (m/z); 474 [M]⁺

EXAMPLE 127(E)-4-[(2-methoxyethoxy)acetyl]-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 127)

The crude product obtained using Compound 18 (200 mg, 0.602 mmol),N-methylmorpholine (0.132 mL, 1.20 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg,0.842 mmol), 1-hydroxybenzotriazole monohydrate (106 mg, 0.783 mmol) and2-methoxyethoxyacetic acid (0.0674 mL, 0.722 mmol) in a similar mannerto Example 5, was purified by silica gel column chromatography(chloroform/methanol=80/20) to obtain Compound 127 (0.011 g, 4%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.25 (s, 3H), 3.40-3.65 (m, 12H), 4.18 (s,1H), 7.22 (t, J=8.1 Hz, 1H), 7.41 (t, J=8.1 Hz, 1H), 7.45 (d, J=7.9 Hz,2H), 7.55 (d, J=16.4 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.65 (d, J=16.4Hz, 1H), 7.80 (d, J=7.9 Hz, 2H), 8.21 (d, J=8.6 Hz, 1H), 13.21 (s, 1H).APCI-MS (m/z); 449 [M]⁺

EXAMPLE 128(E)-4-ethoxyacetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 128)

The crude product obtained using dihydrochloride of Compound 18 (300 mg,0.741 mmol), N-methylmorpholine (0.163 mL, 1.48 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (199 mg,1.04 mmol), 1-hydroxybenzotriazole monohydrate (130 mg, 0.963 mmol) andethoxyacetic acid (0.0700 mL, 0.741 mmol) in a similar manner to Example5, was purified by silica gel column chromatography(chloroform/methanol=90/10), followed by recrystallization from mixedsolvent of ethyl acetate/methanol to obtain Compound 128 (62.0 mg, 20%).

¹H-NMR (300 MHz, DMSO-d₆) δ 1.13 (t, J=6.9 Hz, 3H), 3.40-3.65 (br, 8H),3.47 (q, J=6.9 Hz, 2H), 4.13 (brs, 2H), 7.22 (t, J=7.5 Hz, 1H), 7.41 (t,J=7.5 Hz, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.55 (d, J=16.8 Hz, 1H), 7.56 (d,J=8.4 Hz, 1H), 7.65 (d, J=16.8 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 8.21 (d,J=8.4 Hz, 1H), 13.22 (s, 1H). APCI-MS (m/z); 419 [M]⁺

EXAMPLE 129(E)-4-(3-aminopropionyl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinedihydrochloride (Compound 129)

In a similar manner to Example 5, the product obtained using Compound 18(300 mg, 0.90 mmol), 3-(tert-butoxycarbonylamino)propionic acid (143 mg,0.75 mmol), 1-hydroxybenzotriazole monohydrate (132 mg, 0.98 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg,1.05 mmol) and N-methylmorpholine (0.16 mL, 1.50 mmol) was dissolved inmethanol (2.00 mL), and the solution was added with 4 moL/L hydrogenchloride-methanol solution (1.50 mL), followed by heating under refluxat 60° C. for 40 minutes. The reaction mixture was concentrated underreduced pressure, and the residue was crystallized from acetone toobtain Compound 129 (0.11 mg, 24%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.70-2.75 (m, 2H), 3.01-3.03 (m, 2H), 3.56(br, 8H), 7.22 (dd, J=7.9, 7.9 Hz, 1H), 7.40 (dd, J=7.9, 7.9 Hz, 1H),7.47 (d, J=8.1 Hz, 2H), 7.54 (d, J=7.9 Hz, 1H), 7.55 (d, J=16.8 Hz, 1H),7.65 (d, J=16.8 Hz, 1H), 7.62-7.69 (m, 2H), 7.81 (d, J=8.2 Hz, 2H), 8.20(d, J=8.2 Hz, 1H). APCI-MS (m/z); 404 [M+H]⁺

EXAMPLE 130(E)-4-[(phenylacetylamino)acetyl]-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 130)

In a similar manner to Example 5, Compound 130 (0.21 mg, 46%) wasobtained using Compound 18 (366 mg, 0.90 mmol), phenaceturic acid (175mg, 0.90 mmol), 1-hydroxybenzotriazole monohydrate (132 mg, 0.98 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg,1.05 mmol) and N-methylmorpholine (0.16 mL, 1.50 mmol).

¹H-NMR (270 MHz, DMSO-d₆) 3.56 (br, 10H), 3.99-4.00 (m, 2H), 7.18-7.33(m, 6H), 7.38-7.41 (m, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.55 (d, J=16.6 Hz,1H), 7.65 (d, J=16.6 Hz, 1H), 7.80 (d, J=8.4 Hz, 2H), 8.16 (t, J=5.4 Hz,1H), 8.21 (d, J=8.4 Hz, 1H) 13.2 (br, 1H). APCI-MS (m/z); 508 [M+H]⁺

EXAMPLE 131(E)-4-(2-amino-2-methylpropionyl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinedihydrochrolide (Compound 131)

The product obtained using Compound 18 (300 mg, 0.90 mmol),2-(tert-butoxycarbonyl)amino-2-methylpropionic acid (153 mg, 0.75 mmol),1-hydroxybenzotriazole monohydrate (132 mg, 0.98 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg,1.05 mmol) and N-methylmorpholine (0.16 mL, 1.50 mmol) in a similarmanner to Example 5, was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by heating under reflux at 60° C. for 30 minutes.The reaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 131 (0.10 mg,23%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.57 (br, 6H), 3.65 (br, 4H), 4.36 (br, 4H),7.22 (dd, J=7.9, 7.9 Hz, 1H), 7.41 (dd, J=8.4, 8.4 Hz, 1H), 7.47 (d,J=8.4 Hz, 2H), 7.54 (d, J=7.9 Hz, 1H), 7.55 (d, J=16.6 Hz, 1H), 7.66 (d,J=16.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 8.21 (d, J=8.4 Hz, 1H), 8.27(br, 2H). APCI-MS (m/z); 418 [M+H]⁺

EXAMPLE 132(E)-4-dimethylcarbamoylamino-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperidine(Compound 132)

The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoicacid (200 mg, 0.76 mmol) obtained in Step 6 of Example 1,1,1-dimethyl-3-(piperidin-4-yl)urea (0.20 ml, 1.14 mmol),1-hydroxybenzotriazole monohydrate (133 mg, 1.00 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (204 mg,1.06 mmol) and N-methylmorpholine (0.18 mL, 1.66 mmol) in a similarmanner to Example 5, was crystallized from ethyl acetate to obtainCompound 132 (195 mg, 62%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.38 (br, 2H), 1.75 (br, 2H), 2.77 (s, 6H),3.02 (br, 2H), 3.69 (br, 2H), 4.30 (br, 1H), 6.01 (d, J=7.4 Hz, 1H),7.22 (dd, J=7.4, 7.4 Hz, 1H), 7.38-7.41 (m, 1H), 7.45 (d, 2H, J=8.4 Hz),7.53 (d, J=7.4 Hz, 1H), 7.55 (d, J=16.8 Hz, 1H), 7.65 (d, J=16.8 Hz,1H), 7.80 (d, J=8.4 Hz, 2H), 8.21 (d, J=8.4 Hz, 1H) 13.2 (br, 1H).ESI-MS (m/z); 418 [M+H]⁺

EXAMPLE 134(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-1-(2-methoxyethyl)piperazin-2-onehydrochloride (Compound 134)

The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoicacid (50.0 mg, 0.189 mmol) obtained in Step 6 of Example 1,N-methylmorpholine (0.0415 mL, 0.378 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.7 mg,0.265 mmol), 1-hydroxybenzotriazole monohydrate (33.2 mg, 0.246 mmol)and 1-(2-methoxyethyl)piperazin-2-one (44.8 mg, 0.284 mmol) in a similarmanner to Step 7 of Example 1, was treated with hydrogen chloride-ethylacetate solution (4 mol/L, 0.236 mL) to obtain Compound 134 (10.0 mg,12%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.26 (s, 3H), 3.40-3.55 (m, 4H), 3.60-4.20(br, 6H), 7.22 (t, J=7.0 Hz, 1H), 7.40 (t, J=7.0 Hz, 1H), 7.48 (d, J=7.4Hz, 2H), 7.55 (d, J=17.0 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.66 (d,J=17.0 Hz, 1H), 7.81 (d, J=7.4 Hz, 2H), 8.21 (d, J=7.6 Hz, 1H). APCI-MS(m/z); 405 [M+H]⁺

EXAMPLE 135(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-[2-oxo-2-(isopropylamino)ethyl]piperazinedihydrochloride (Compound 135)

The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoicacid (200 mg, 0.757 mmol) obtained in Step 6 of Example 1,N-methylmorpholine (0.166 mL, 1.51 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (203 mg,1.06 mmol), 1-hydroxybenzotriazole monohydrate (133 mg, 0.984 mmol)and-N-isopropyl-2-(piperazin-1-yl)acetamide (210 mg, 1.14 mmol) in asimilar manner to Step 7 of Example 1, was purified by silica gel columnchromatography (chloroform/methanol=80/20), followed by treating with 4mol/L hydrogen chloride-ethyl acetate solution (0.665 mL) to obtainCompound 135 (99.7 mg, 26%).

¹H-NMR (300 MHz, DMSO-d₆) δ 1.10 (d, J=6.9 Hz, 1H), 3.20-3.65 (br, 8H),3.95 (s, 2H), 4.03 (q, J=6.9 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.50 (d,J=8.4 Hz, 2H), 7.56 (d, J=16.5 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.67 (d,J=16.5 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 8.22 (d, J=8.1 Hz, 1H), 8.67 (d,J=7.5 Hz, 1H), 10.61 (brs, 1H). APCI-MS (m/z); 432 [M+H]⁺

EXAMPLE 136(E)-4-(3-hydroxy-2-hydroxymethyl-2-methylpropionyl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinehydrochloride (Compound 136)

The crude product obtained using dihydrochloride of Compound (300 mg,0.741 mmol), N-methylmorpholine (0.163 mL, 1.48 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (199 mg,1.04 mmol), 1-hydroxybenzotriazole monohydrate (130 mg, 0.963 mmol) and3-hydroxy-2-hydroxymethyl-2-methylpropionic acid (99.4 mg, 0.741 mmol)in a similar manner to Example 5, was purified by silica gel columnchromatography (chloroform/methanol=80/20), followed by treating with10% hydrogen chloride-methanol solution (0.932 mL) and tritirating inacetone to obtain Compound 136 (10.0 mg, 3%).

¹H-NMR (300 MHz, DMSO-d₆) δ 3.17 (brs, 3H), 3.60-3.85 (br, 4H),4.00-4.45 (br, 8H), 7.22 (t, J=7.2 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.50(d, J=8.4 Hz, 2H), 7.56 (d, J=16.5 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.66(d, J=16.5 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 8.21 (d, J=8.1 Hz, 1H), 9.14(br.s, 1H).

EXAMPLE 137(E)-4-[4-(acetylamino)butyryl]-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 137)

In a similar manner to Example 5, Compound 137 (0.12 mg, 52%) wasobtained using dihydrochloride of Compound 18 (200 mg, 0.49 mmol),4-acetylaminobutyric acid (72 mg, 0.49 mmol), 1-hydroxybenzotriazolemonohydrate (87 mg, 0.64 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (133 mg,0.69 mmol) and N-methylmorpholine (0.11 mL, 0.98 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.63 (t, J=6.9 Hz, 2H), 1.79 (s, 3H),2.31-2.34 (m, 2H), 3.04 (q, J=6.9 Hz, 2H), 3.51 (br, 8H), 7.22 (dd,J=7.4, 7.4 Hz, 1H), 7.38-7.41 (m, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.53 (d,J=7.4 Hz, 1H), 7.55 (d, J=16.8 Hz, 1H), 7.65 (d, J=16.8 Hz, 1H), 7.80(d, J=8.4 Hz, 2H), 8.21 (d, J=8.4 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z);460 [M+H]⁺

EXAMPLE 138(E)-4-(N-acetyl-N-methylaminoacetyl)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 138)

The crude product obtained using dihydrochloride of Compound 18 (300 mg,0.741 mmol), N-methylmorpholine (0.163 mL, 1.48 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (199 mg,1.04 mmol), 1-hydroxybenzotriazole monohydrate (130 mg, 0.963 mmol) andN-acetylsarcosine (77.7 mg, 0.593 mmol) In a similar manner to Example5, was purified by silica gel column chromatography(chloroform/methanol=90/10), followed by triturating in mixed solvent ofethyl acetate/methanol to obtain Compound 138 (54.8 mg, 25%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.02 (s, 3H), 2.97 (s, 3H), 3.42-3.60 (br,8H), 4.18 (s, 2H), 7.22 (t, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.46(d, J=8.1 Hz, 2H), 7.55 (d, J=16.7 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.66(d, J=16.7 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 8.21 (d, J=8.1 Hz, 1H),13.21 (s, 1H). APCI-MS (m/z); 446 [M]⁺

EXAMPLE 139(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-1-(cyclopropyl)piperazine-2,6-dione(Compound 139)

In a similar manner to Example 5, Compound 139 (64 mg, 28%) was obtainedusing (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (150 mg, 0.57 mmol)obtained in Step 6 of Example 1, 1-(cyclopropyl)piperazine-2,6-dione(100 mg, 0.86 mmol), 1-hydroxybenzotriazole monohydrate (100 mg, 0.74mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153mg, 0.80 mmol) and N-methylmorpholine (0.13 mL, 1.14 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 0.57-0.64 (m, 2H), 0.86-0.94 (m, 2H),2.43-2.49 (m, 1H), 4.44 (br, 4H), 7.23 (dd, J=7.2, 7.2 Hz, 1H), 7.41(dd, J=7.2, 7.2 Hz, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.56 (d, J=16.8 Hz,1H), 7.57 (d, J=8.2 Hz, 1H), 7.68 (d, J=16.8 Hz, 1H), 7.83 (d, J=8.2 Hz,2H), 8.21 (d, J=8.2 Hz, 1H), 13.2 (br, 1H). APCI-MS (m/z); 401 [M+H]⁺

EXAMPLE 140(S)-(E)-4-[(pyrrolidin-2-yl)carbonyl]-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 140)

The product obtained using dihydrochloride of Compound 18 (100 mg, 0.25mmol), N-(tert-butoxycarbonyl)-L-proline (53 mg, 0.25 mmol),1-hydroxybenzotriazole monohydrate (43 mg, 0.33 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (66 mg, 0.35mmol) and N-methylmorpholine (0.06 mL, 0.50 mmol) in a similar manner toExample 5, was dissolved in methanol (2.00 mL), and the solution wasadded with 4 moL/L hydrogen chloride-methanol solution (1.50 mL)followed by heating under reflux at 60° C. for 30 minutes. The reactionmixture was concentrated under reduced pressure, and the residue wasadded with saturated sodium hydrogencarbonate solution and ethylacetate, followed by extraction. The crude product was crystallized fromacetone to obtain Compound 140 (21 mg, 20%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.85-1.91 (m, 4H), 2.32-2.36 (m, 2H),3.14-3.21 (m, 4H), 3.57 (br, 4H), 4.52 (br, 1H), 7.22 (dd, J=7.4, 7.4Hz, 1H), 7.41 (dd, J=8.2, 8.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.53 (d,J=7.4 Hz, 1H), 7.56 (d, J=16.6 Hz, 1H), 7.66 (d, J=16.6 Hz, 1H), 7.81(d, J=8.2 Hz, 2H), 8.21 (d, J=8.2 Hz, 1H), 13.2 (br, 1H). APCI-MS (m/z);430 [M+H]⁺

EXAMPLE 141(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-1-(2-methoxyethyl)piperazine-2,6-dione(Compound 141)

In a similar manner to Example 5, Compound 141 (155 mg, 49%) wasobtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (200 mg,0.76 mmol) obtained in Step 6 of Example 1,1-(2-methoxyethyl)piperazine-2,6-dione (200 mg, 1.14 mmol),1-hydroxybenzotriazole monohydrate (134 mg, 0.99 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (204 mg,1.06 mmol) and N-methylmorpholine (0.17 mL, 1.52 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.23 (s, 3H), 3.41 (t, J=6.3 Hz, 2H), 3.84(t, J=6.3 Hz, 2H), 4.51 (br, 4H), 7.23 (dd, J=7.1, 7.1 Hz, 1H), 7.41(dd, J=8.1, 8.1 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 1H),7.58 (d, J=16.8 Hz, 1H), 7.69 (d, J=16.8 Hz, 1H), 7.84 (d, J=8.1 Hz,2H), 8.22 (d, J=8.1 Hz, 1H), 13.2 (br, 1H). APCI-MS (m/z); 419 [M+H]⁺

EXAMPLE 142(E)-4-[(piperidin-4-yl)carbonyl]-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinedihydrochloride (Compound 142)

The product obtained using dihydrochloride of Compound 18 (200 mg, 0.49mmol), isonipecotic acid tert-butyl ester (122 mg, 0.49 mmol),1-hydroxybenzotriazole monohydrate (86 mg, 0.64 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (132 mg,0.69 mmol) and N-methylmorpholine (0.1 mL, 0.98 mmol) in a similarmanner to Example 5, was dissolved in methanol (2.00 mL), and thesolution was added with 4 moL/L hydrogen chloride-methanol solution(1.50 mL), followed by heating under reflux at 60° C. for 30 minutes.The reaction mixture was concentrated under reduced pressure, and theresidue was crystallized from acetone to obtain Compound 142 (0.09 mg,41%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.76 (br, 6H), 2.94 (br, 2H), 3.25-3.63 (m,9H), 7.22 (dd, J=7.4, 7.4 Hz, 1H), 7.40 (dd, J=7.4, 7.4 Hz, 1H), 7.46(d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 1H), 7.55 (d, J=16.8 Hz, 1H), 7.66(d, J=16.8 Hz, 1H), 7.81 (d, J=8.2 Hz, 2H), 8.21 (d, J=8.2 Hz, 1H), 8.56(br, 1H), 8.83 (br, 1H). ESI-MS (m/z); 444 [M+H]⁺

EXAMPLE 143(E)-4-[(1-methylpiperidin-4-yl)carbonyl]-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 143)

In a similar manner to Example 5, Compound 143 (0.02 mg, 9%) wasobtained using dihydrochloride of Compound 18 (200 mg, 0.49 mmol),1-methylpiperidin-4-carboxylic acid (70 mg, 0.49 mmol),1-hydroxybenzotriazole monohydrate (86 mg, 0.64 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (132 mg,0.69 mmol) and N-methylmorpholine (0.10 mL, 0.98 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.58-1.59 (m, 4H), 1.91 (br, 2H), 2.15 (s,3H), 2.76-2.80 (m, 2H), 3.51 (br, 9H), 7.22 (dd, J=7.7, 7.7 Hz, 1H),7.39 (dd, J=7.7, 7.7 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz,1H), 7.55 (d, J=16.6 Hz, 1H), 7.65 (d, J=16.6 Hz, 1H), 7.80 (d, J=8.4Hz, 2H), 8.21 (d, J=8.4 Hz, 1H), 13.2 (br, 1H). ESI-MS (m/z); 458 [M+H]⁺

EXAMPLE 144(E)-4-[N,N-di(2-hydroxyethyl)aminoacetyl]-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazinedihydrochloride (Compound 144)

The crude product obtained using dihydrochloride of Compound 18 (150 mg,0.370 mmol) N-methylmorpholine (0.0812 mL, 0.740 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (99.3 mg,0.370 mmol), 1-hydroxybenzotriazole monohydrate (64.9 mg, 0.481 mmol)and di(hydroxyethyl)aminoacetic acid (60.4 mg, 0.370 mmol) in a similarmanner to Example 5, was purified by C-18 column chromatography(water/methanol=67/33), followed by treating with 10% hydrogenchloride-methanol solution (0.775 mL) and triturating in ethyl acetateto obtain Compound 144 (43.5 mg, 21%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.72-7.76 (brm, 2H), 3.20-3.25 (brm, 4H),3.22-3.26 (brm, 4H), 3.60-3.80 (br, 8H), 7.21 (t, J=8.1 Hz, 1H), 7.40(d, J=8.1 Hz, 1H), 7.49 (d, J=7.8 Hz, 2H), 7.54 (d, J=18.6 Hz, 1H), 7.56(d, J=9.4 Hz, 1H), 7.65 (d, J=18.6 Hz, 1H), 7.80 (d, J=7.8 Hz, 2H), 8.20(d, J=9.4 Hz, 1H), 8.94 (brs, 1H). ESI-MS (m/z); 417 [M−C₂H₄O₂]⁺

EXAMPLE 145(E)-4-[(1-methylpyrrolidin-2-yl)carbonyl]-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 145)

In a similar manner to Step 1 of Example 1, Compound 145 (97 mg, 87%)was obtained using Compound 18 (83 mg, 0.25 mmol), N-methylprolinemonohydrate (44 mg, 0.30 mmol), 1-hydroxybenzotriazole monohydrate (110mg, 0.83 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (160 mg, 0.85 mmol) and N-methylmorpholine (0.12 mL, 1.10mmol).

¹H-NMR (270 MHz, CDCl₃) δ 1.75-2.31 (m, 6H), 2.38 (s, 3H), 3.16-3.22 (m,1H), 3.30-4.00 (m, 8H), 7.21-7.28 (m, 1H), 7.36-7.42 (m, 1H), 7.43 (d,J=8.3 Hz, 2H), 7.50-7.52 (m, 3H), 7.61 (d, J=8.3 Hz, 2H), 8.02 (d, J=8.2Hz, 2H). APCI-MS (m/z); 444 [M+H]⁺

EXAMPLE 146(E)-4-[(4-methylmorpholin-2-yl)carbonyl]-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 146)

In a similar manner to Step 1 of Example 1, Compound 146 (60 mg, 52%)was obtained using Compound 18 (100 mg, 0.25 mmol),4-methylmorpholine-2-carboxylic acid hydrochloride (56 mg, 0.30 mmol),1-hydroxybenzotriazole monohydrate (56 mg, 0.40 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (82 mg, 0.43mmol) and N-methylmorpholine (0.16 mL, 1.4 mmol).

¹H-NMR (270 MHz, CDCl₃) δ 2.17-2.27 (m, 1H), 2.35-2.44 (m, 4H), 2.67(brd, J=11.4 Hz, 1H), 2.90 (brd, J=11.8 Hz, 1H), 3.30-4.00 (m, 10H),4.25-4.28 (m, 1H), 7.21-7.28 (m, 1H), 7.36-7.51 (m, 6H), 7.60 (d, J=8.2Hz, 2H), 8.02 (d, J=8.2 Hz, 1H). APCI-MS (m/z); 460 [M+H]⁺

EXAMPLE 147(E)-4-Hydroxy-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine(Compound 147)

Compound 18 (0.35 g, 1.1 mmol) was dissolved in methanol (2.1 mL) andwas added with a 31% hydrogen peroxide solution (0.13 g, 1.1 mmol),followed by stirring at room temperature for 1 hour. The reactionmixture was added with sodium hydrogen sulfite (0.1 g, 0.96 mmol), andthen the deposited crystals were removed by filtration after confirmingthe disappearance of hydrogen peroxide using a potassium iodide-starchpaper. The solvent of the filtrate was evaporated under reducedpressure, the crude product was purified by preparative silica gelchromatography [amino-modified chemically bound silica gel Chromatorex(registered trademark) NH, Fuji Silysia Chemical Ltd.,methanol/chloroform=1/9] to obtain Compound 147 (57 mg, 15%).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.44-2.52 (m, 4H), 2.95-3.29 (brm, 4H), 7.28(brt, J=7.5 Hz, 1H), 7.44-7.50 (m, 3H), 7.60 (d, J=16.7 Hz, 1H),7.61-7.63 (m, 1H), 7.70 (d, J=16.7 Hz, 1H), 7.84 (d, J=8.4 Hz, 2H), 8.27(d, J=8.2 Hz, 1H), 8.30 (s, 1H), 13.1-13.4 (m, 1H). APCI-MS (m/z); 349[M+H]⁺

EXAMPLE 148(E)-1-{4-+[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(tert-butyloxycarbonylamino)piperazine(Compound 148)

In a similar manner to Step 1 of Example 1, Compound 148 (97 mg, 87%)was obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (66 mg,0.25 mmol) obtained in Step 6 of Example 1,1-(tert-butyloxycarbonylamino)piperazine (60 mg, 0.30 mmol) obtained ina similar manner to the method described in WO98/35951,1-hydroxybenzotriazole monohydrate (44 mg, 0.32 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 0.35mmol) and N-methylmorpholine (55 μL, 0.50 mmol).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.39 (s, 9H), 2.66-2.82 (m, 4H), 3.30-3.72(m, 4H), 7.22 (brt, J=7.2 Hz, 1H), 7.38-7.43 (m, 3H), 7.54 (d, J=16.8Hz, 1H), 7.56 (d, J=7.4 Hz, 1H), 7.64 (d, J=16.8 Hz, 1H), 7.79 (d, J=8.2Hz, 2H), 8.20 (d, J=8.1 Hz, 1H), 13.2 (brs, 1H). APCI-MS (m/z); 448[M+H]⁺

EXAMPLE 149(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-aminopiperazine (Compound149)

In a similar manner to Example 18, Compound 149 (28 mg, 42%) wasobtained using Compound 148 (85 mg, 0.19 mmol), methanol (0.19 mL) and10% hydrogen chloride-methanol solution (0.38 mL).

¹H-NMR (300 MHz, CDCl₃) δ 2.46-2.82 (m, 4H), 3.40-4.00 (m, 4H),7.22-7.27 (m, 1H), 7.37-7.48 (m, 4H), 7.51 (s, 2H), 7.59 (brd, J=8.1 Hz,2H), 8.02 (d, J=8.1 Hz, 1H), 10.8-12.0 (m, 1H). APCI-MS (m/z); 348[M+H]⁺

EXAMPLE 150(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-4-(morpholinocarbonylamino)piperazine(Compound 150)

In a similar manner to Step 1 of Example 1, Compound 150 (87 mg, 74%)was obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (68 mg,0.26 mmol) obtained in Step 6 of Example 1,1-morpholinocarbonylaminopiperazine (65 mg, 0.30 mmol),1-hydroxybenzotriazole monohydrate (46 mg, 0.33 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg, 0.35mmol) and N-methylmorpholine (56 μL, 0.51 mmol).

¹H-NMR (270 MHz, CD₃OD) δ 2.69-2.95 (m, 4H), 3.35-3.39 (m, 4H),3.62-3.86 (m, 8H), 7.22-7.28 (m, 1H), 7.40-7.47 (m, 3H), 7.53-7.57 (m,3H), 7.75 (brd, J=8.3 Hz, 2H), 8.12 (d, J=8.3 Hz, 1H). APCI-MS (m/z);461 [M+H]⁺

EXAMPLE 151(E)-3-amino-4-{[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-3-cyclobutene-1,2-dione(Compound 151)

Step 1

(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine (1.0 g, 2.5 mmol)obtained in Example 18 was dissolved in methanol (9.9 mL), and thesolution was added with 3,4-diisopropoxy-3-cyclobutene-1,2-dione (0.69g, 3.5 mmol) and triethylamine (0.69 mL, 4.9 mmol), followed by stirringat room temperature for 13 hours. The reaction mixture was concentratedunder reduced pressure, and the crude product was added with ethanol,followed by stirring. The deposited crystal was collected by filtrationto obtain(E)-3-{4-[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-4-isopropoxy-3-cyclobutene-1,2-dione(0.94 g, 81%).

Step 2

(E)-3-{4-[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-4-isopropoxy-3-cyclobutene-1,2-dione(87 mg, 0.19 mmol) obtained in Step 1 was dissolved in methanol (0.74mL) and DMF (0.5 mL), and the solution was added with ammonium chloride(100 mg, 1.9 mmol) and triethylamine (0.26 mL, 1.9 mmol), followed bystirring, at 50° C. for 4 hours. The reaction was stopped by addition ofsaturated aqueous sodium hydrogencarbonate solution, and the reactionmixture was extracted with chloroform (100 mL×2). The organic layer waswashed with saturated brine, and was dried over anhydrous sodiumsulfate, and then the solvent was evaporated under reduced pressure. Thecrude product was crystallized from methanol (5 mL) to obtain Compound151 (16.3 mg, 21%).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.45-3.90 (m, 8H), 7.22 (brt, J=7.5 Hz, 1H),7.41 (brt, J=7.2 Hz, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.55 (d, J=16.7 Hz,1H), 7.57 (d, J=10.0 Hz, 1H), 7.66 (d, J=16.7 Hz, 1H), 7.75 (br s, 2H),7.81 (d, J=8.3 Hz, 2H), 8.21 (d, J=8.1 Hz, 1H), 13.2 (brs, 1H). APCI-MS(m/z); 426 [M−H]⁻

EXAMPLE 152(E)-3-methylamino-4-{[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-3-cyclobutene-1,2-dione(Compound 152)

In a similar manner to Step 2 of Example 151, Compound 152 (112 mg,100%) was obtained using(E)-3-{4-[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-4-isopropoxy-3-cyclobutene-1,2-dione(120 mg, 0.25 mmol) obtained in Step 1 of Example 151, 40%methylamine-methanol solution (0.16 mL, 1.9 mmol) and DMF (0.99 mL).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.18 (s, 3H), 3.50-3.82 (m, 8H), 7.19-7.24(m, 1H), 7.37-7.43 (m, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.55 (d, J=16.9 Hz,1H), 7.56 (d, J=6.7 Hz, 1H), 7.66 (d, J=16.9 Hz, 1H), 7.80 (d, J=8.2 Hz,2H), 8.21 (d, J=8.2 Hz, 1H). APCI-MS (m/z); 442 [M+H]⁺

EXAMPLE 153(E)-3-dimethylamino-4-{[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-3-cyclobutene-1,2-dione(Compound 153)

In a similar manner to Step 2 of Example 151, Compound 153 (94 mg, 87%)was obtained using(E)-3-{4-[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-4-isopropoxy-3-cyclobutene-1,2-dione(110 mg, 0.24 mmol) obtained in Step 1 of Example 151, 2.0 mol/Ldimethylamine-methanol solution (0.90 mL, 1.8 mmol) and DMF (0.95 mL).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.17 (s, 6H), 3.48-3.85 (m, 8H), 7.20-7.25(m, 1H), 7.38-7.44 (m, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.55 (d, J=16.6 Hz,1H), 7.57 (d, J=9.7 Hz, 1H), 7.66 (d, J=16.6 Hz, 1H), 7.81 (d, J=8.2 Hz,2H), 8.21 (d, J=8.1 Hz, 1H), 13.2 (brs, 1H). APCI-MS (m/z); 456 [M+H]⁺

EXAMPLE 154(E)-3-(pyrrolidin-1-yl)-4-{[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-3-cyclobutene-1,2-dione(Compound 154)

In a similar manner to Step 2 of Example 151, Compound 154 (97 mg, 93%)was obtained using(E)-3-{4-[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-4-isopropoxy-3-cyclobutene-1,2-dione(100 mg, 0.22 mmol) obtained in Step 1 of Example 151, pyrrolidine (0.14mL, 1.6 mmol) and DMF (0.86 mL).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.84-1.89 (m, 4H), 3.49-3.91 (m, 12H),7.19-7.25 (m, 1H), 7.38-7.43 (m, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.55 (d,J=16.7 Hz, 1H), 7.57 (d, J=9.9 Hz, 1H), 7.66 (d, J=16.7 Hz, 1H), 7.81(d, J=8.2 Hz, 2H), 8.21 (d, J=8.1 Hz, 1H), 13.2 (brs, 1H). APCI-MS(m/z); 482 [M+H]⁺

EXAMPLE 155(E)-3-piperidino-4-{[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-3-cyclobutene-1,2-dione(Compound 155)

In a similar manner to Step 2 of Example 151, Compound 155 (93 mg, 87%)was obtained using(E)-3-{4-[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-4-isopropoxy-3-cyclobutene-1,2-dione(100 mg, 0.22 mmol) obtained in Step 1 of Example 151, piperidine (0.16mL, 1.6 mmol) and DMF (0.86 mL).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.57-1.65 (m, 6H), 3.47-3.85 (m, 12H),7.20-7.25 (m, 1H), 7.38-7.43 (m, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.55 (d,J=16.7 Hz, 1H), 7.57 (d, J=9.7 Hz, 1H), 7.66 (d, J=16.7 Hz, 1H), 7.81(d, J=8.2 Hz, 2H), 8.21 (d, J=8.2 Hz, 1H), 13.2 (brs, 1H). APCI-MS(m/z); 496 [M+H]⁺

EXAMPLE 156(E)-3-morpholino-4-{[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-3-cyclobutene-1,2-dione(Compound 156)

In a similar manner to Step 2 of Example 151, Compound 156 (79 mg, 74%)was obtained using(E)-3-{4-[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-4-isopropoxy-3-cyclobutene-1,2-dione(100 mg, 0.21 mmol) obtained in Step 1 of Example 151, morpholine (0.14mL, 1.6 mmol) and DMF (0.86 mL).

¹H-NMR (270 MHz, DMSO-d₆) δ 3.57-3.83 (m, 16H), 7.19-7.25 (m, 1H),7.37-7.43 (m, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.55 (d, J=16.7 Hz, 1H), 7.57(d, J=8.2 Hz, 1H), 7.66 (d, J=16.7 Hz, 1H), 7.81 (d, J=8.2 Hz, 2H), 8.21(d, J=8.2 Hz, 1H). APCI-MS (m/z); 498 [M+H]⁺

EXAMPLE 157(E)-3-(4-methylpiperazin-1-yl)-4-{[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-3-cyclobutene-1,2-dione(Compound 157)

In a similar manner to Step 2 of Example 151, Compound 157 (49 mg, 45%)was obtained using(E)-3-{4-[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-4-isopropoxy-3-cyclobutene-1,2-dione(100 mg, 0.21 mmol) obtained in Step 1 of Example 151 andN-methylpiperazine (0.18 mL, 1.6 mmol) and DMF (0.86 mL).

¹H-NMR (270 MHz, DMSO-d₆) δ 2.20 (s, 3H), 2.38-2.42 (m, 4H), 3.52-3.82(m, 12H), 7.19-7.25 (m, 1H), 7.37-7.43 (m, 1H), 7.46 (d, J=8.1 Hz, 2H),7.55 (d, J=16.9 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.66 (d, J=16.9 Hz,1H), 7.81 (d, J=8.1 Hz, 2H), 8.21 (d, J=8.2 Hz, 1H). APCI-MS (m/z); 511[M+H]⁺

EXAMPLE 158(R)-(E)-1-{4-[2-(1H-Indazol-3-yl)vinyl]benzoyl}-3-aminopyrrolidine(Compound 158)

The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid(700 mg, 2.65 mmol) obtained in Step 6 of Example 1, tert-butyl(R)-(pyrrolidin-3-yl)carbamate (740 mg, 3.98 mmol),1-hydroxybenzotriazole monohydrate (470 mg, 3.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (710 mg,3.72 mmol) and N-methylmorpholine (0.608 mL, 5.32 mmol) in a similarmanner to Example 5, was dissolved in methanol (1.5 mL), and thesolution was added with a 4 mol/L solution of hydrogen chloride inmethanol (1.50 mL), followed by heating under reflux at 60° C. for 60minutes. The reaction mixture was concentrated under reduced pressure,the residue was added with saturated aqueous potassium carbonatesolution and ethyl acetate and was extracted. The crude product wascrystallized from ethyl acetate to obtain Compound 158 (506 mg, 58%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.59-1.99 (m, 4H), 3.08-3.18 (m, 1H),3.67-3.78 (m, 4H), 7.22 (dd, J=7.6, 7.6 Hz, 1H), 7.40 (dd, J=7.6, 7.6Hz, 1H), 7.51-7.57 (m, 4H), 7.64 (d, J=16.8 Hz, 1H), 7.77 (d, J=8.2 Hz,2H), 8.21 (d, J=8.2 Hz, 1H), 13.2 (brs, 1H). APCI-MS (m/z); 333 [M+H]⁺

EXAMPLE 159(S)-(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}-3-aminopyrrolidine(Compound 159)

The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid(700 mg, 2.65 mmol) obtained in Step 6 of Example 1,(S)-(pyrrolidin-3-yl)carbamic acid tert-butyl ester (740 g, 3.98 mmol),1-hydroxybenzotriazole monohydrate (470 mg, 3.46 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (710 mg,3.72 mmol) and N-methylmorpholine (0.608 mL, 5.32 mmol) in a similarmanner to Example 5, was dissolved in methanol (1.5 mL) and the solutionwas added with 4 moL/L hydrogen chloride-methanol solution (1.50 mL),followed by heating under reflux at 60° C. for 60 minutes. The reactionmixture was concentrated under reduced pressure, and the residue wasadded with saturated aqueous sodium hydrogencarbonate solution and ethylacetate, followed by extraction. The crude product was crystallized fromacetone to obtain Compound 159 (190 mg, 22%).

¹H-NMR (270 MHz, DMSO-d₆) δ 1.59-1.99 (m, 4H), 3.08-3.18 (m, 1H),3.67-3.78 (m, 4H), 7.22 (dd, J=7.6, 7.6 Hz, 1H), 7.40 (dd, J=7.6, 7.6Hz, 1H), 7.51-7.57 (m, 4H), 7.64 (d, J=16.8 Hz, 1H), 7.77 (d, J=8.2 Hz,2H), 8.21 (d, J=8.2 Hz, 1H), 13.2 (brs, 1H). APCI-MS (m/z); 333 [M+H]⁺

EXAMPLE 160 Preparation Example (Tablet)

Tablet having the following formulation is prepared in a conventionalmanner. Compound 2 5 mg Lactose 60 mg  Potato starch 30 mg  Poly(vinylalcohol) 2 mg Magnesium stearate 1 mg Tar pigment trace amount

INDUSTRIAL APPLICABILITY

The present invention provides indazole derivatives or pharmaceuticallyacceptable salts thereof which have antitumor activities or the like.

1. An indazole derivative represented by Formula (I)

wherein R¹ represents CONR^(1a)R^(1b) (wherein R^(1a) and R^(1b) may bethe same or different and each represents a hydrogen atom, substitutedor unsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted aralkyl, or a substituted or unsubstitutedheterocyclic group, or R^(1a) and R^(1b) are combined together with theadjacent nitrogen atom thereto to form a substituted or unsubstitutedheterocyclic group) or NR^(1c)R^(1d) (wherein R^(1c) representssubstituted or unsubstituted lower alkylsulfonyl or substituted orunsubstituted arylsulfonyl and R^(1d) represents a hydrogen atom orsubstituted or unsubstituted lower alkyl) and R² represents a hydrogenatom, halogen, cyano, nitro, hydroxy, carboxy, lower alkoxycarbonyl,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower alkoxy, substituted or unsubstituted lower alkanoyl,CONR^(2a)R^(2b) (wherein R^(2a) and R^(2b) may be the same or differentand each represents a hydrogen atom, substituted or unsubstituted loweralkyl, substituted or unsubstituted aryl, substituted or unsubstitutedaralkyl or a substituted or unsubstituted heterocyclic group, or R^(2a)and R^(2b) are combined together with the adjacent nitrogen atom theretoto form a substituted or unsubstituted heterocyclic group) orNR^(2c)R^(2d) (wherein R^(2c) and R^(2d) may be the same or differentand each represents a hydrogen atom, substituted or unsubstituted loweralkyl, substituted or unsubstituted lower alkanoyl, substituted orunsubstituted aroyl, substituted or unsubstituted heteroaroyl,substituted or unsubstituted aralkyl, substituted or unsubstituted loweralkylsulfonyl or substituted or unsubstituted arylsulfonyl), or apharmaceutically acceptable salt thereof.
 2. The indazole derivative orthe pharmaceutically acceptable salt thereof according to claim 1,wherein R¹ is CONR^(1a)R^(1b) and R² is a hydrogen atom or substitutedor unsubstituted lower alkoxy.
 3. The indazole derivative or thepharmaceutically acceptable salt thereof according to claim 1, whereinR¹ is NR^(1c)R^(1d) and R² is substituted or unsubstituted lower alkoxy.4. The indazole derivative or the pharmaceutically acceptable saltthereof according to claim 1, wherein R¹ is CONR^(1a)R^(1b) and R² ishalogen or substituted or unsubstituted lower alkyl.
 5. The indazolederivative or the pharmaceutically acceptable salt thereof according toclaim 1, wherein R¹ is NR^(1c)R^(1d) and R² is a hydrogen atom.
 6. Apharmaceutical composition which comprises, as an active ingredient, theindazole derivative or the pharmaceutically acceptable salt thereofaccording to any of claims 1 to
 5. 7-18. (canceled)
 19. A method fortreating tumor, comprising a step of administering an effective amountof the indazole derivative or the pharmaceutically acceptable saltthereof according to any of claims 1 to
 5. 20. A method for treatinghematopoietic tumor, comprising a step of administering an effectiveamount of the indazole derivative or the pharmaceutically acceptablesalt thereof according to any of claims 1 to
 5. 21. A method fortreating leukaemia, comprising a step of administering an effectiveamount of the indazole derivative or the pharmaceutically acceptablesalt thereof according to any of claims 1 to
 5. 22. A method fortreating myeloma or lymphoma, comprising a step of administering aneffective amount of the indazole derivative or the pharmaceuticallyacceptable salt thereof according to any of claims 1 to
 5. 23. A methodfor treating solid carcinoma, comprising a step of administering aneffective amount of the indazole derivative or the pharmaceuticallyacceptable salt thereof according to any of claims 1 to
 5. 24. A methodfor treating cancer derived from mammary cancer, uterine body cancer,uterine cervix cancer, prostatic cancer, bladder cancer, renal cancer,gastric cancer, esophageal cancer, hepatic cancer, biliary tract cancer,colon cancer, rectal cancer, pancreatic cancer, lung cancer, oral cavityand pharynx cancer, osteosarcoma, melanoma or brain neoplasm, comprisinga step of administering an effective amount of the indazole derivativeor the pharmaceutically acceptable salt thereof according to any ofclaims 1 to 5.